Atropisomers of 3-heteroaryl-4(3H)-quinazolinones for the treatment of neurodegenerative and CNS-trauma related conditions

ABSTRACT

The present invention relates to novel atropisomers of 3-heteroaryl-4(3H)-quinazolinones of the formula Ia, and their pharmaceutically acceptable salts, and pharmaceutical compositions and methods of treating neurodegenerative and CNS-trauma related conditions.

This is a national stage application under 35 USC §371 of PCTInternational Application No. PCT/IB98/00151, filed Feb. 6, 1998, whichclaims the benefit of Ser. No. 60/038,540, filed Feb. 28, 1997.

BACKGROUND OF THE INVENTION

The present invention relates to atropisomers of3-heteroaryl-4(3H)-quinazolinones of the formula Ia, described below,and their pharmaceutically acceptable salts, and pharmaceuticalcompositions and methods of treating neurodegenerative and CNS-traumarelated conditions.

Atropisomers are isomeric compounds that are chiral, i.e. each isomer isnot superimposable on its mirror image and the isomers, once separated,rotate polarized light in equal amounts but opposite directions.Atropisomers are distinguished from enantiomers in that atropisomers donot possess a single asymmetric atom. Atropisomers are conformationalisomers which occur when rotation about a single bond in the molecule isprevented or greatly slowed as a result of steric interactions withother parts of the molecule and the substituents at both ends of thesingle bond are unsymmetrical. A detailed account of atropisomers can befound in Jerry March, Advanced Organic Chemistry, 101-102 (4th ed. 1992)and in Oki, Top. Stereochem., 14, 1-81 (1983).

The compounds of the invention provide the first evidence thatatropisomers of quinazolinones are separable and that the separatedisomers possess differential AMPA receptor antagonist activity. (AMPAreceptors are a subspecies of glutamate receptors, identified by theirability to bind α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid(AMPA), that are post-synaptic neurotransmitter receptors for excitatoryamino acids.) Colebrook et al., Can. J. Chem., 53, 3431-4, (1975)observed hindered rotation about aryl C═N bonds in quinazolinones butdid not separate or suggest that the rotational isomers could beseparated. U.S. patent application Ser. No. 60/017,738 filed May 15,1996and entitled “Novel 2,3-Disubstituted-4-(3H)-Quinazolinones” and U.S.patent application Ser. No. 60/017,737 filed May 15, 1996 and entitled“Novel 2,3-Disubstituted-(5,6)-Heteroarylfused-Pyrimidin-4-ones,” bothapplications herein incorporated by reference in there entirety, referto racemic quinazolinones and pyrimidinones. Suprisingly, the inventorsof the present invention have discovered that one quinazolinone isomer,defined by the spatial positions of the substituents arising out ofsteric interactions, possesses all of the AMPA receptor antagonistactivity.

The role of excitatory amino acids, such as glutamic acid and asparticacid, as the predominant mediators of excitatory synaptic transmissionin the central nervous system has been well established. Watkins &Evans, Ann. Rev. Pharmacol. Toxicol., 21, 165 (1981); Monaghan,Bridges,and Cotman, Ann. Rev. Pharmacol. Toxicol., 29, 365 (1989);Watkins, Krogsgaard-Larsen, and Honore, Trans. Pharm. Sci., 11, 25(1990). These amino acids function in synaptic transmission primarilythrough excitatory amino acid receptors. These amino acids alsoparticipate in a variety of other physiological processes such as motorcontrol, respiration, cardiovascular regulation, sensory perception, andcognition.

Excitatory amino acid receptors are classified into two general types.Receptors that are directly coupled to the opening of cation channels inthe cell membrane of the neurons are termed “ionotropic.” This type ofreceptor has been subdivided into at least three subtypes, which aredefined by the depolarizing actions of the selective agonistsN-methyl-D-aspartate (NMDA),α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), and kainicacid (KA). The second general type is the G-protein or secondmessenger-linked “metabotropic” excitatory amino acid receptor. Thissecond type, when activated by the agonists quisqualate, ibotenate, ortrans-1-aminocyclopentane-1,3-dicarboxylic acid, leads to enhancedphosphoinosoitide hydrolysis in the postsynaptic cell. Both types ofreceptors appear not only to mediate normal synaptic transmission alongexcitatory pathways, but also participate in the modification ofsynaptic connection during development and changes in the efficiency ofsynaptic transmission throughout life. Schoepp, Bockaert, and Sladeczek.Trends in Pharmacol. Sci., 11, 508 (1990); McDonald and Johnson, BrainResearch Reviews, 15, 41 (1990).

The excessive or inappropriate stimulation of excitatory amino acidreceptors leads to neuronal cell damage or loss by way of a mechanismknown as excitotoxicity. This process has been suggested to mediateneuronal degeneration in a variety of conditions. The medicalconsequences of such neuronal degeneration makes the abatement of thesedegenerative neurological processes an important therapeutic goal.

Excitatory amino acid excitotoxicity has been implicated in thepathophysiology of a number of neurological disorders. Thisexcitotoxicity has been implicated in the pathophysiology of acute andchronic neurodegenerative conditions including cerebral deficitssubsequent to cardiac bypass surgery and grafting, stroke, cerebralischemia, spinal cord trauma, head trauma, Alzheimer's Disease,Huntington's Chorea, amyotrophic lateral sclerosis, epilepsy,AIDS-induced dementia, perinatal hypoxia, hypoxia (such as conditionscaused by strangulation, surgery, smoke inhalation, asphyxiation,drowning, choking, electrocution or drug or alcohol overdose), cardiacarrest, hypoglycemic neuronal damage, ocular damage and retinopathy, andidiopathic and drug-induced Parkinson's Disease. Other neurologicalconditions, that are caused by glutamate dysfunction, requireneuromodulation. These other neurological conditions include muscularspasms, migraine headaches, urinary incontinence, psychosis, addictionwithdrawal (such as alcoholism and drug addiction including opiate,cocaine and nicotine addiction), opiate tolerance, anxiety, emesis,brain edema, chronic pain, convulsions, retinal neuropathy, tinnitus andtardive dyskinesia. The use of a neuroprotective agent, such as an AMPAreceptor antagonist, is believed to be useful in treating thesedisorders and/or reducing the amount of neurological damage associatedwith these disorders. The excitatory amino acid receptor (EAA)antagonists are also useful as analgesic agents.

Several studies have shown that AMPA receptor antagonists areneuroprotective in focal and global ischemia models. The competitiveAMPA receptor antagonist NBQX(2,3-dihydroxy-6-nitro-7-sulfamoylbenzo[f-]quinoxaline) has beenreported effective in preventing global and focal ischemic damage.Sheardown et al., Science, 247, 571 (1900); Buchan et al., Neuroreport,2, 473 (1991); LePeillet et al., Brain Research, 571, 115 (1992). Thenoncompetitive AMPA receptor antagonists GKYI 52466 has been shown to bean effective neuroprotective agent in rat global ischemia models.LaPeillet et al., Brain Research, 571, 115 (1992). These studiesstrongly suggest that the delayed neuronal degeneration in brainischemia involves glutamate excitotoxicity mediated at least in part byAMPA receptor activation. Thus, AMPA receptor antagonists may proveuseful as neuroprotective agents and improve the neurological outcome ofcerebral ischemia in humans.

SUMMARY OF THE INVENTION

The present invention relates to an atropisomer of the formula

wherein each of “A, B and D” is nitrogen or —CH—, with the proviso thatonly one of “A”, “B” and “D” can be nitrogen; wherein n is an integerfrom one to four, preferably one to or two, and wherein each R⁵ is asubstituent on any carbon atom of the “A, B, D” ring capable ofsupporting an additional bond, with the proviso that one R⁵ must beattached to a carbon atom ortho to the asterisked carbon of the ring;wherein each R⁵ may be independently selected from the group consistingof (C₁-C₆)alkyl, halogen, trifluoromethyl, amino-(CH₂)_(m)—,(C₁-C₆)alkylamino-(CH₂)_(m)—, di(C₁-C₆)alkyl-amino-(CH₂)_(m)—,(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl-, (C₁-C₆)alkyl-O—(C₁-C₆)alkyl-, —CN,hydroxy-(CH₂)_(m)—, (C₁-C₆)alkyl-(O═C)—O—(C₁-C₆)alkyl-,(C₁-C₆)alkyl-O—(C═O)—O—(C₁-C₆)alkyl, (C₁-C₆)alkyl-(O═C)—O—,H—(C═O)—(CH₂)_(m)—, (C₁-C₆)alkyl-(C═O)—(CH₂)_(m)—, HO—(C═O)—,(C₁-C₆)alkyl-O—(C═O)—(CH₂)_(m)—, NH₂—(C═O)—(CH₂)_(m)—,(C₁-C₆)alkyl-NH—(C═O)—(CH₂)_(m)—, and di(C₁-C₆)alkyl-N—(C═O)—(CH₂)_(m)—;and wherein m is an integer from zero to four;

R² is a phenyl group of the formula Ph² or a five or six memberedheterocycle;

wherein said 6-membered heterocycle has the formula

wherein “N” is nitrogen; wherein said ring positions “K”, “L” and “M”may be independently selected from carbon and nitrogen, with the provisothat i) only one of “K”, “L” and “M” can be nitrogen and ii) when “K”,“L” or “M” is nitrogen, then its respective R¹⁵, R¹⁶ or R¹⁷ is absent;

wherein said five membered heterocycle has the formula

wherein said “T” is —CH—, N, NH, O or S; wherein said ring positions “P”and “Q” may be independently selected from carbon, nitrogen, oxygen andsulfur; with the proviso that only one of “P,” “Q” or “T” can be oxygenor sulfur and at least one of “P”, “Q” or “T” must be a heteroatom;

wherein said Ph² is a group of the formula

R³ is hydrogen, halo, —CN, —NO₂, CF₃, (C₁-C₆)alkyl or (C₁-C₆)alkoxy;

R⁹ is hydrogen, halo, CF₃, (C₁-C₆)alkyl optionally substituted with oneto three halogen atoms, (C₁-C₆)alkoxy optionally substituted with one tothree halogen atoms, (C₁-C₆)alkylthiol, amino-(CH₂)_(s)—,(C₁-C₆)alkyl-NH—(CH₂)_(s)—, di(C₁-C₆)alkyl-N—(CH₂)_(s)—,(C₃-C₇)cycloalkyl-NH—(CH₂)_(s)—, H₂N—(C═O)—(CH₂)_(s)—,(C₁-C₆)alkyl-HN—(C═O)—(CH₂)_(s)—, di(C₁-C₆)alkyl-N—(C═O)—(CH₂)_(s)—,(C₃-C₇)cycloalkyl-NH—(C═O)—(CH₂)_(s)—, R¹³O—(CH₂)_(s)—,R¹³O—(C═O)—(CH₂)_(s)—, H(O═C)—NH—(CH₂)_(s)—,(C₁-C₆)alkyl-(O═C)—NH—(CH₂)_(s)—,

 H—(C═O)—(CH₂)_(s)—, (C₁-C₆)alkyl-(C═O)—, hydroxy,hydroxy-(C₁-C₆)alkyl-, (C₁-C₆)alkyl-O—(C₁-C₆)alkyl-, or —CN;

R¹⁰ is hydrogen or halo;

R¹¹ and R¹⁴ are selected, independently, from hydrogen, halo, CF₃,(C₁-C₆)alkyl optionally substituted with one to three halogen atoms,(C₁-C₆)alkoxy optionally substituted with one to three halogen atoms,(C₁-C₆)alkylthiol, amino-(CH₂)_(p)—, (C₁-C₆)alkyl-NH—(CH₂)_(p)—,di(C₁-C₆)alkyl-N—(CH₂)_(p)—, (C₃-C₇)cycloalkyl-NH—(CH₂)_(p)—,amino-C₁-C₆)alkyl-NH—(CH₂)_(p)—,(C₁-C₆)alkyl-NH—(C₁-C₆)alkyl-NH—(CH₂)_(p)—,di(C₁-C₆)alkyl-N—(C₁-(C₆)alkyl-NH—(CH₂)_(p)—,

 H₂N—(C═O)—(CH₂)_(p)—, (C₁-C₆)alkyl-HN—(C═O)—(CH₂)_(p)—,di(C₁-C₆)alkyl-N—(C═O)—(CH₂)_(p), (C₃-C₇)cycloalkyl-NH—(C═O)—(CH₂)_(p)—,R¹³O—(CH₂)_(p)—, R¹³O—(C═O)—(CH₂)_(p)—, H(O═C)—O—,H(O═C)—O—(C₁-C₆)alkyl-, H(O═C)—NH—(CH₂)_(p)—,(C₁-C₆)alkyl-(O═C)—NH—(CH₂)_(p)—, —CHO, H—(C═O)—(CH₂)_(p)—, (C₁-C₆)alkyl-(C═O)—(CH₂)_(p)—,

 (C₁-C₆)alkyl-(C═O)—O—(CH₂)_(p)—, amino-(C₁-C₆)alkyl-(C═O)—O—(CH₂)_(p)—,(C₁-C₆)alkyl-NH—(C₁-C₆)alkyl-(C═O)—O—(CH₂)_(p)—,di(C₁-C₆)alkyl-N—(C₁-C₆)alkyl-(C═O)—O—(CH₂)_(p)—,amino-(C₁-C₆)alkyl-O—(C═O)—(CH₂)_(p)—,(C₁-C₆)alkyl-NH—(C₁-C₆)alkyl-O—(C═O)—(CH₂)_(p)—,di(C₁-C₆)alkyl-N—(C₁-C₆)alkyl-O—(C═O)—(CH₂)_(p)—, hydroxy,hydroxy-(C₁-C₆)alkyl-, hydroxy-(C₁-C₆)alkyl-NH—(CH₂)_(p)—,(C₁-C₆)alkyl-O—(C₁-C₆)alkyl-, —CN, piperidine-(CH₂)_(p)—,pyrrolidine-(CH₂)_(p)—, and 3-pyrroline-(CH₂)_(p)—, wherein saidpiperidine, pyrrolidine and 3-pyrroline moieties of saidpiperidine-(CH₂)_(p)—, pyrrolidine-(CH₂)_(p)— and 3-pyrroline-(CH₂)_(p)—groups may optionally be substituted on any of the ring carbon atomscapable of supporting an additional bond, preferably zero to twosubstituents, with a substituent independently selected from halo, CF₃,(C₁-C₆)alkyl optionally substituted with one to three halogen atoms,(C₁-C₆)alkoxy optionally substituted with one to three halogen atoms,(C₁-C₆)alkylthiol, amino-(CH₂)_(p)—, (C₁-C₆)alkyl-NH—(CH₂)_(p)—,di(C₁-C₆)alkyl-N—(CH₂)_(p)—, (C₃-C₇)cycloalkyl-NH—(CH₂)_(p)—,amino-(C₁-C₆)alkyl-NH—(CH₂)_(p)—,(C₁-C₆)akyl-NH—(C₁-C₆)alkyl-NH—(CH₂)_(p)—,di(C₁-C₆)alkyl-N—(C₁-C₆)alkyl-, NH—(CH₂)_(p)—, (C₁—C₆)alkyl-O—(C₁-C₆)aklyl-,

 H₂N—(C═O)—(CH₂)_(p)—, (C₁-C₆)alkyl-HN—(C═O)-(CH₂)_(p)—,di(C₁-C₆)alkyl-N—(C═O)—(CH₂)_(p), (C₃-C₇)cycloalkyl-NH—(C═O)—(CH₂)_(p)—,R¹³O—(CH₂)_(p)—, R¹³O—(C═O)—(CH₂)_(p)—, H(O═C)—O—,H(O═C)—O—(C₁-C₆)alkyl-, H(O═C)—NH—(CH₂)_(p)—,(C₁-C₆)alkyl-(O═C)—NH—(CH₂)_(p)—, —CHO, H—(C═O)—(CH₂)_(p)—,(C₁-C₆)alkyl-(C═O)—,

 (C₁-C₆)alkyl-(C═O)—O—NH—(CH₂)_(p)—,amino-(C₁-C₆)alkyl-(C═O)—O—(CH₂)_(p)—,(C₁-C₆)alkyl-NH—(C₁-C₆)alkyl-(C═O)—O—(CH₂)_(p)—,di(C₁-C₆)alkyl-N—(C₁-C₆)alkyl-(C═O)—O—(CH₂)_(p)—, hydroxy,hydroxy-(C₁-C₆)alkyl-, hydroxy-(C₁-C₆)alkyl-NH—(CH₂)_(p)—, and —CN;

R¹² is hydrogen, —CN or halo;

R¹³ is hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkyl-(C═O)—,(C₁-C₆)alkyl-O—(C═O)—, (C₁-C₆)alkyl-NH(C₁-C₆)alkyl,di(C₁-C₆)-alkyl-N—(C₁-C₆)alkyl-, (C₁-C₆)alkyl-NH—(C═O)—, ordi(C₁-C₆)alkyl-N—(C═O)—;

R¹⁵ is hydrogen, —CN, (C₁-C₆)alkyl, halo, CF₃, —CHO or (C₁-C₆)alkoxy;

R¹⁶ is hydrogen, —CN, (C₁-C₆)alkyl, halo, CF₃, —CHO or (C₁-C₆)alkoxy;

R¹⁷ is hydrogen, —CN, (C₁-C₆)alkyl, amino-(C₁-C₆)alkyl-,(C₁-C₆)alkyl-NH—(C₁-C₆)alkyl-, di(C₁-C₆)alkyl-N—(C₁-C₆)alkyl-, halo,CF₃, —CHO or (C₁-C₆)alkoxy;

each p is independently an integer from zero to 4;

s is an integer from zero to 4;

wherein the dashed bond represented an optional double bond;

and the pharmaceutically acceptable salts of such compounds.

The present invention also relates to the pharmaceutically acceptableacid addition salts of compounds of the formula I. The acids which areused to prepare the pharmaceutically acceptable acid addition salts ofthe aforementioned base compounds of this invention are those which formnon-toxic acid addition salts, i.e., salts containing pharmacologicallyacceptable anions, such as the hydrochloride, hydrobromide, hydroiodide,nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate,lactate, citrate, acid citrate, tartrate, bitartrate, succinate,maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate,ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)]salts.

The invention also relates to base addition salts of formula I. Thechemical bases that may be used as reagents to prepare pharmaceuticallyacceptable base salts of those compounds of formula I that are acidic innature are those that form non-toxic base salts with such compounds.Such non-toxic base salts include, but are not limited to those derivedfrom such pharmacologically acceptable cations such as alkali metalcations (e.g., potassium and sodium) and alkaline earth metal cations(e.g., calcium and magnesium), ammonium or water-soluble amine additionsalts such as N-methylglucamine (meglumine), and the loweralkanolammonium and other base salts of pharmaceutically acceptableorganic amines.

Preferred compounds of formula I are those wherein R³ is hydrogen, haloor (C₁-C₆)alkyl.

Other preferred compounds of formula Ia are those wherein “B” isnitrogen and “A” and “D” are carbon and R⁵ is hydrogen, halo, —CN, CF₃,or (C₁-C₆)alkyl, preferably R⁵ is chloro or methyl, more preferably R⁵is a substituent ortho to the asterisked carbon.

Preferred compounds of formula Ia wherein R² is Ph² are those wherein R⁹is fluoro, chloro, —CN or hydroxy; or R¹¹ is —CHO, chloro, fluoro,methyl, (C₁-C₆)alkyl-NH—(CH₂)_(p)—, di(C₁-C₆)alkyl-N—(CH₂)_(p)—,pyrrolidine-(CH₂)_(p)— or cyano. Most preferred compounds of formula Iawherein R² is Ph² are those wherein R⁹ is fluoro or —CN; or R¹¹ ismethyl, (C₁-C₆)alkyl-NH—(CH₂)_(p)—, di(C₁-C₆)alkyl-N—(CH₂)_(p)—, orcyano.

Preferred compounds of formula Ia wherein R² is heteroaryl are thosewherein said heteroaryl is either an optionally substituted six-memberedheterocycle wherein “K”, “L” and “M” are carbon (i.e. pyridin-2-yl), or“K” and “L” are carbon and “M” is nitrogen (i.e. pyrimidin-2-yl), orsaid heteroaryl is an optionally substituted five membered heterocyclewherein “T” is nitrogen, “P” is sulfur and “Q” is carbon (i.e.1,3-thiazol-4-yl), or “T” is nitrogen or sulfur, “Q” is nitrogen orsulfur and “P” is carbon (i.e. 1,3-thiazol-2-yl) or “T” is oxygen and“P” and “Q” are each carbon (i.e. fur-2-yl).

Preferred compounds of formula Ia wherein R²is an optionally substitutedsix-membered heterocycle wherein “K”, “L” and “M” are carbon (i.e.pyridin-2-yl) are those wherein R¹⁴ is hydrogen, —CHO, chloro, fluoro,methyl, (C₁-C₆)alkyl-NH—(CH₂)_(p)—, di(C₁-C₆)alkyl-N—(CH₂)_(p)—,pyrrolidine-(CH₂)_(p)— or cyano; R¹⁷ is hydrogen, —CHO, chloro, fluoro,methyl, (C₁-C₆)alkyl-NH—(C₁-C₆)alkyl, di(C₁-C₆)alkyl-N—(C₁-C₆)alkyl, orcyano; or R¹⁵ or R¹⁶ are independently hydrogen, —CHO, chloro, fluoro,methyl or cyano. Most preferred compounds of formula Ia wherein R² is anoptionally substituted six-membered heterocycle wherein “K”, “L” and “M”are carbon (i.e. pyridin-2-yl) are those wherein R¹⁴ is hydrogen, —CHO,methyl, (C₁-C₆)alkyl-NH—(CH₂)_(p)—, di(C₁-C₆)alkyl-N—(CH₂)_(p)—, orcyano.

Preferred compounds of formula Ia wherein R² is an optionallysubstituted five-membered heterocycle wherein “T” is nitrogen, “P” issulfur and “Q” is carbon (i.e. 1,3-thiazol-4-yl) are those wherein R¹⁴,R¹⁵ or R¹⁶ i.e., are each independently hydrogen, chloro, fluoro, methylor cyano.

Preferred compounds of formula Ia wherein R² is an optionallysubstituted five-membered heterocycle wherein “T” is nitrogen or sulfur,“Q” is sulfur or nitrogen and “P” is carbon (i.e. 1,3-thiazol-2-yl) arethose wherein R¹⁴ or R¹⁵ are independently hydrogen, chloro, fluoro,methyl or cyano.

Examples of specific preferred compounds of formula Ia include:

(S)-6-fluoro-2-[2-(2-fluoro-phenyl)-vinyl]-3-(2-methyl-pyridin-3-yl)-3H-quinazolin-4-one;

(S)-2-{2-[6-fluoro-3-(2-methyl-pyridin-3-yl)-4-oxo-3,4-dihydro-quinazolin-2-yl]-vinyl}-benzonitrile;

(S)-2-{2-[6-fluoro-3-(2-methylpyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl]-vinyl}-benzonitrile;

(S)-2-{2-[3-(2-chloro-pyridin-3-yl)-6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl]-vinyl}-benzonitrile;

(S)-2-{2-[6-fluoro-3-(2-methyl-pyridin-3-yl)-4-oxo-3,4-dihydro-quinazolin-2-yl]-vinyl}-4-methyl-benzonitrile;

(S)-2-{2-[3-(2-methyl-pyridin-3-yl)-4-oxo-3,4-dihydro-quinazolin-2-yl]-vinyl}-benzonitrile;

(S)-6-fluoro-3-(2-methyl-pyridin-3-yl)-2-[2-(2-thiazol-4-yl)-vinyl]-3H-quinazolin-4-one;

(S)-6-fluoro-3-(2-methyl-pyridin-3-yl)-2-[2-(2-methyl-thiazol-4-yl)-vinyl]-3H-quinazolin-4-one;

(S)-6-fluoro-3-(2-methyl-pyridin-3-yl)-2-[2-(4-methyl-thiazol-2-yl)-vinyl]-3H-quinazolin-4-one;

(S)-2-[2-(5-diethylaminomethyl-2-fluoro-phenyl)-vinyl]-6-fluoro-3-(2-methyl-pyridin-3-yl)-3H-quinazolin-4-one;and

(S)-6-fluoro-2-[2-(2-fluoro-5-pyrrolidin-1-ylmethyl-phenyl)-vinyl]-3-(2-methyl-pyridin-3-yl)-3H-quinazolin-4-one.

Other compounds of the invention include:

(S)-3-(2-chloro-pyridin-3-yl)-2-[2-(2-fluoro-phenyl)-vinyl]-3H-quinazolin-4-one;

(S)-3-(2-chloro-pyridin-3-yl)-6-fluoro-2-[2-(6-methyl-phenyl-2-yl)-vinyl]-3H-quinazolin-4-one;

(S)-3-(2-chloro-pyridin-3-yl)-6-fluoro-2-[2-(fluoro-phenyl)-vinyl]-3H-quinazolin-4-one;

(S)-6-chloro-2-[2-(2-fluoro-phenyl)-vinyl]-3-(2-methyl-pyridin-3-yl)-3H-quinazolin-4-one;

(S)-6-chloro-2-[2-(2-fluoro-phenyl)-vinyl]-3-(3methyl-1-oxy-pyridin-4-yl)-3H-quinazolin-4-one;

(S)-3-{2-[3-(2-chloro-pyridin-3-yl)-6-fluoro-4-oxo-3,4-dihydro-quinazolin-2-yl]-vinyl}-benzaldehyde;

(S)-3-{2-[3-(2-chloro-pyridin-3-yl)-4-oxo-3,4-dihydro-quinazolin-2-yl]-vinyl}-benzaldehyde;

(S)-3-(2-chloro-pyridin-3-yl)-6-fluoro-2-[2-(3-hydroxymethyl-phenyl)-vinyl]-3H-quinazolin-4-one;

(S)-3-(2-chloro-pyridin-3-yl)-2-{2-[3(1,4-dioxa-8-aza-spiro[4.5]dec-8-ylmethyl)-phenyl]-vinyl}-6-fluoro-3H-quinazolin-4-one;

(S)-3-(2-chloro-pyridin-3-yl)-6-fluoro-2-{2-[3-(4-pyrrolidin-1-yl-piperidin-1-ylmethyl)-phenyl]-vinyl}-3H-quinazolin-4-one;

(S)-2-{2-[3-(2-chloro-pyridin-3-yl-6-fluoro-4-oxo-3,4-dihydro-quinazolin-2-yl]-vinyl}-benzonitrile;

(S)-2-{2-[3-(2-chloro-pyridin-3-yl)-4-oxo-3,4-dihydro-quinazolin-2-yl]-vinyl}-benzonitrile;

(S)-2-[2-(2-fluoro-phenyl)-vinyl]-3-(2-methyl-pyridin-3-yl)-3H-quinazolin-4-one;

(S)-3-(2-chloro-pyridin-3-yl)-6-fluoro-2-[2-hydroxy-phenyl)-vinyl]-3H-quinazolin-4-one;

(S)-6-fluoro-3-(2-methyl-pyridin-3-yl)-2-[2-(2-methyl-thiazol-4-yl)-ethyl]-3H-quinazolin-4-one;

(S)-6-fluoro-3-(2-chloro-pyridin-3-yl)-2-[2-(2-dimethylamino-methylthiazo-4-yl)-vinyl]-3H-quinazolin-4-one;

(S)-2-[2-(5-Diethylaminomethyl-2-fluoro-phenyl)-vinyl]-6-fluoro-3-(4-methyl-pyridin-3-yl)-3H-quinazolin-4-one

(S)-4-Diethylaminomethyl-2-(2-[6-fluoro-3-(4-methyl-pyridin-3-yl)-4-oxo-3,4-dihydro-quinazolin-2-yl]-vinyl}-benzonitrile

(S)-2-[2-(5-Diethylaminomethyl-2-fluoro-phenyl)-vinyl]-6-fluoro-3-(3-methyl-pyrazin-2-yl)-3H-quinazolin-4-one

(S)-6-fluoro-3-(2-methyl-pyridin-3-yl)-2-[2-(2-dimethylamino-methylthiazol-4-yl)-vinyl]-3H-quinazolin-4-one;

(S)-6-fluoro-3-(2-methyl-pyridin-3-yl)-2-[2-(2-methyl-oxazol-4-yl)-vinyl]-3H-quinazolin-4-one;

(S)-6-fluoro-3-(2-chloro-pyridin-3-yl)-2-[2-(2-thiazol-4-yl)-vinyl]-3H-quinazolin-4-one;

(S)-6-fluoro-3-(4-methyl-pyridin-3-yl)-2-[2-(4-methyl-thiazol-2-yl)-vinyl]-3H-quinazolin-4-one;

(S)-3-(2-chloro-pyridin-3-yl)-6-fluoro-2-[2-(2-hydroxy-phenyl)-vinyl]-3H-quinazolin-4-one;and

(S)-6-fluoro-2-[2-(2-fluoro-5-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-3-(2-methyl-pyridin-3-yl)-3H-quinazolin-4-one.

This invention also relates to a pharmaceutical composition for treatingor preventing a condition selected from cerebral deficits subsequent tocardiac bypass surgery and grafting, stroke, cerebral ischemia, spinalcord trauma, head trauma, Alzheimer's Disease, Huntington's Chorea,amyotrophic lateral sclerosis, epilepsy, AIDS-induced dementia,perinatal hypoxia, hypoxia (such as conditions caused by strangulation,surgery, smoke inhalation, asphyxiation, drowning, choking,electrocution or drug or alcohol overdose), cardiac arrest, hypoglycemicneuronal damage, opiate tolerance, addiction withdrawal (such asalcoholism and drug addiction including opiate, cocaine and nicotineaddiction), idiopathic and drug induced Parkinson's Disease and brainedema, and muscular spasms, migraine headaches, urinary incontinence,psychosis, convulsions, chronic or acute pain, ocular damage,retinopathy, retinal neuropathy, tinnitus, anxiety, emesis and tardivedyskinesia, in a mammal, comprising an amount of a compound of formulaIa effective in treating or preventing such condition and apharmaceutically acceptable carrier.

This invention also relates to a method of treating or preventing acondition selected from cerebral deficits subsequent to cardiac bypasssurgery and grafting, stroke, cerebral ischemia, spinal cord trauma,head trauma, Alzheimer's Disease, Huntington's Chorea, amyotrophiclateral sclerosis, epilepsy, AIDS-induced dementia, perinatal hypoxia,hypoxia (such as conditions caused by strangulation, surgery, smokeinhalation, asphyxiation, drowning, choking, electrocution or drug oralcohol overdose), cardiac arrest, hypoglycemic neuronal damage, opiatetolerance, addiction withdrawal (such as alcoholism and drug addictionincluding opiate, cocaine and nicotine addiction), idiopathic and druginduced Parkinson's Disease and brain edema, and muscular spasms,migraine headaches, urinary incontinence, psychosis, convulsions,chronic or acute pain, ocular damage, retinopathy, retinal neuropathy,tinnitus, anxiety, emesis and tardive dyskinesia, in a mammal,comprising administering to a mammal in need of such treatment orprevention an amount of a compound of formula Ia effective in treatingor preventing such condition.

This invention also relates to a pharmaceutical composition for treatingor preventing a condition selected from cerebral deficits subsequent tocardiac bypass surgery and grafting, stroke, cerebral ischemia, spinalcord trauma, head trauma, Alzheimer's Disease, Huntington's Chorea,amyotrophic lateral sclerosis, epilepsy, AIDS-induced dementia,perinatal hypoxia, hypoxia (such as conditions caused by strangulation,surgery, smoke inhalation, asphyxiation, drowning, choking,electrocution or drug or alcohol overdose), cardiac arrest, hypoglycemicneuronal damage, opiate tolerance, addiction withdrawal (such asalcoholism and drug addiction including opiate, cocaine and nicotineaddiction), idiopathic and drug induced Parkinson's Disease and brainedema, and muscular spasms, migraine headaches, urinary incontinence,psychosis, convulsions, chronic or acute pain, ocular damage,retinopathy, retinal neuropathy, tinnitus, anxiety, emesis and tardivedyskinesia, in a mammal, comprising an AMPA receptor antagonizingeffective amount of a compound of formula Ia and a pharmaceuticallyacceptable carrier.

This invention also relates to a method for treating or preventing acondition selected from cerebral deficits subsequent to cardiac bypasssurgery and grafting, stroke, cerebral ischemia, spinal cord trauma,head trauma, Alzheimer's Disease, Huntington's Chorea, amyotrophiclateral sclerosis, epilepsy, AIDS-induced dementia, perinatal hypoxia,hypoxia (such as conditions caused by strangulation, surgery, smokeinhalation, asphyxiation, drowning, choking, electrocution or drug oralcohol overdose), cardiac arrest, hypoglycemic neuronal damage, opiatetolerance, addiction withdrawal (such as alcoholism and drug addictionincluding opiate, cocaine and nicotine addiction), idiopathic and druginduced Parkinson's Disease and brain edema, and muscular spasms,migraine headaches, urinary incontinence, psychosis, convulsions,chronic or acute pain, ocular damage, retinopathy, retinal neuropathy,tinnitus, anxiety, emesis and tardive dyskinesia, in a mammal,comprising administering to a mammal requiring such treatment orprevention an AMPA receptor antagonizing effective amount of a compoundof formula Ia.

The compounds of this invention include all stereoisomers and alloptical isomers of compounds of the formula Ia (e.g., R and Senantiomers), as well as racemic, diastereomeric and other mixtures ofsuch isomers.

The compounds of this invention may contain olefin-like double bonds.When such bonds are present, the compounds of the invention exist as cisand trans configurations and as mixtures thereof.

Unless otherwise indicated, the alkyl groups referred to herein, as wellas the alkyl moieties of other groups referred to herein (e.g., alkoxy),may be linear or branched, and they may also be cyclic (e.g.,cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) or be linear orbranched and contain cyclic moieties.

Unless otherwise indicated, halo or halogen refer to fluorine, bromine,chlorine or iodine.

The bold lines in formulae Ia and Ib, depicted below, indicate that thebolded atoms, and the groups attached thereto, are sterically restrictedso as to exist either orthogonally above the plane of the quinazolinonering or orthogonally below the plane of the quinazolinone ring. Thissteric restriction is due to a rotational energy barrier preventing freerotation about the single bond connecting the quinazolinone ring to the“A, B and D” containing ring. This rotational energy barrier is a resultof an inability of a R⁵ substituent, ortho to the asterisked carbon, torotate around the quinazoline nucleus.

In the compounds of formula Ia, the atoms “A and B” and the substituentsthereon are sterically restricted so as to exist orthogonally above theplane of the quinazolinone ring when the ring is laid out with the vinylgroup to the right of the quinazolinone ring. Compounds of formula Iaare denoted with (S) stereochemistry. In the compounds of formula Ib,the mirror image of the compounds of formula Ia and drawn below, theatoms “A, B and D” are sterically restricted so as to exist orthogonallyabove the plane of the quinazolinone ring when the vinyl group is laidout to the left of the quinazolinone ring. Compounds of the formula Ibare denoted with (R) stereochemistry. The compounds of formula Iapossess substantially all of the AMPA receptor antagonist activitywhereas the compounds of formula Ib are essentially devoid of AMPAreceptor antagonist activity.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of formula I can be prepared according to the methods ofScheme 1. In the reaction Scheme and discussion that follow, A, B. D, K,L, M, P, Q, T, R², R³, R⁵, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷,Ph², n, m, p, and s unless otherwise indicated, are as defined above forformula Ia.

Scheme 1 refers to the preparation of compounds of the formula Ia or Ibfrom compounds of the formula V. Compounds of the formula V arecommercially available or can be prepared by methods well known to thoseof ordinary skill in the art.

A compound of the formula V can be converted into an acetamide of theformula IV by reaction with acetyl chloride or acetic anhydride in thepresence of a base in a reaction inert solvent. Suitable solventsinclude methylene chloride, dichloroethane, tetrahydrofuran and dioxane,preferably methylene chloride. Suitable bases include trialkylaminessuch as triethylamine and tributylamine, dimethylaminopyridine andpotassium carbonate, preferably triethylamine. The temperature of theaforesaid reaction is in the range from about 0° C. to about 35° C. forabout 1 hour to about 10 hours, preferably at about 25° C. for about 3hours.

The acetamide of the formula IV is cyclized to a compound of the formulaIII by reaction with a dehydrating agent, in the presence of a catalyst,in dry reaction inert solvent. Suitable dehydrating agents includeacetic anhydride, phosphrous pentoxide, dicyclohexylcarbodimide, andacetyl chloride, preferably acetic anhydride. Suitable catalysts includesodium or potassium acetate, acetic acid, p-toluene sulfonic acid, orboron trifluoride etherate, preferably sodium acetate. Suitable solventsinclude dioxane, toluene, diglyme or dichloroethane, preferably dioxane.The temperature of the aforesaid reaction is in the range from about 80°C. to about 110° C. for about 1 hour to about 24 hours, preferably atabout 100° C. for about 3 to 10 hours.

Alternatively, the compound of formula V can be directly converted intoa compound of formula III by reaction with acetic anhydride in thepresence of an acid catalyst in a solvent. Suitable acid catalystsinclude acetic acid, sulfuric acid, or p-toluene sulfonic acid,preferably acetic acid. Suitable solvents include acetic acid, tolueneor xylene, preferably acetic acid. The temperature of the aforesaidreaction is from about 20° C. to about 150° C. for about 10 minutes toabout 10 hours, preferably at about 120° C. for about 2 to 5 hours.

The compound of formula II, formed by either of the above methods, isreacted with an amine of the formula

in a polar protic solvent in the presence of an acid catalyst to form acompound of the formula II. Suitable acid catalysts include acetic acid,p-toluene sulfonic acid or sulfuric acid, preferably acetic acid.Suitable polar protic solvents include acetic acid, methanol, ethanol orisopropanol, preferably acetic acid. The temperature of the aforesaidreaction is from about 20° C. to about 117° C. for about 1 hour to about24 hours, preferably at about 117° C. for about 6 hours.

Alternatively, a compound of the formula IV can be directly converted toa compound of the formula II by reaction with a dehydrating agent, anamine of the formula VIII, and a base, in a reaction inert solvent.Suitable dehydrating agents include phosphorous trichloride, phosphorousoxychloride, phosphorous pentachloride or thionyl chloride, preferablyphosphorous trichloride. Suitable bases include pyridine, lutidine,dimethylaminopyridine, triethylamine or N-methyl morpholine, preferablypyridine. Suitable solvents include toluene, cyclohexane, benzene orxylene, preferably toluene. Under some circumstances, when the combinedreactants are a liquid, the reaction may be run neat. The temperature ofthe aforesaid reaction is from about 50° C. to about 150° C. for about 1hour to about 24 hours, preferably at about 110° C. for about 4 hours.

The compound of formula II is reacted with an aldehyde of the formulaR²CHO in the presence of a catalyst and a dehydrating agent in asuitable solvent to form a compound of the formula I, wherein the dashedline is double bond. Suitable catalysts include zinc chloride, sodiumacetate, aluminum chloride, tin chloride, or boron trifluoride etherate,preferably zinc chloride or sodium acetate. Suitable dehydrating agentsinclude acetic anhydride, methane sulfonic anhydride, trifluoroaceticanhydride or propionic anhydride, preferably acetic anhydride. Suitablepolar solvents include acetic acid, dioxane, dimethoxyethane orpropionic acid. The temperature of the aforesaid reaction is from about60° C. to about 100° C. for about 30 minutes to about 24 hours,preferably at about 100° C. for about 3 hours.

Compounds of the formula I wherein the dashed line represents a singlecarbon-carbon bond may be prepared by hydrogenating the correspondingcompounds wherein the dashed line represents a double carbon-carbonbond, using standard techniques that are well known to those skilled inthe art. For example, reduction of the double bond may be effected withhydrogen gas (H₂), using catalysts such as palladium on carbon (Pd/C),palladium on barium sulfate (Pd/BaSO₄), platinum on carbon (Pt/C), ortris(triphenylphosphine) rhodium chloride (Wilkinson's catalyst), in anappropriate solvent such as methanol, ethanol, THF, dioxane or ethylacetate, at a pressure from about 1 to about 5 atmospheres and atemperature from about 10° C. to about 60° C., as described in CatalyticHydrogenation in Organic Synthesis, Paul Rylander, Academic Press Inc.,San Diego, 1979, pp. 31-63. The following conditions are preferred: Pdon carbon, ethyl acetate at 25° C. and 15-20 psi of hydrogen gaspressure. This method also provides for introduction of hydrogenisotopes (i.e. deuterium, tritium) by replacing ¹H₂ with ²H₂ or ³H₂ inthe above procedure.

Compounds of the formula I can be separated into compounds of theformulae Ia and Ib by High Pressure Liquid Chromatography (HPLC) using achiral HPLC column and eluting with an appropriate solvent. One ofordinary skill in the art will understand that many types ofinstruments, columns and eluents can be used to separate the individualatropisomers. Suitable HPLC instruments include LC SpiderLing®, Waters4000®, Hewlett Packard 1050® and Analytical Grade Thermo SeparationProducts HPLC. Suitable HPLC's are configured according to methods wellknown to those of ordinary skill in the art. Such configurationinvariably includes a pump, injection port and a detector. Suitablechiral columns can be purchased prepackaged or can be packed by one ofordinary skill in the art. Suitable chiral columns include chiral OA,OD, OG, AD and AS columns which can be purchased from ChiralTechnologies Inc., 730 Springdale Drive, PO Box 564, Exton, Pa. 19341.One of ordinary skill in the art will appreciate that many other chiralcolumns, purchased from other vendors, would be adequate to separate theisomers of the invention. The packing material can also be purchased indifferent bead sizes. Suitable bead sizes for preparative separationsare about 20 microns in diameter. Suitable bead sizes for analyticalseparation are about 10 microns in diameter.

Compounds of formula Ia, wherein a basic group is present, can also beresolved by treatment with an enantiomerically pure acid in a suitablesolvent to form separable diasteriomeric salts. Suitableenantiomerically pure acids include camphor sulphonic acid, tartaricacid (and derivatives thereof), mandelic acid and lactic acid. Suitablesolvents include alcohols, such as ethanol, methanol and butanol,toluene, cyclohexane, ether and acetone.

Alternatively, a compound of the formula V can be converted to acompound of the formula II according to the methods described in Scheme2. The compound of formula II, so formed, can be converted into acompound of formula I according to the methods of Scheme 1. Referring toScheme 2, a compound of the formula V is reacted with a couplingreagent, an amine of the formula VIII, and a base in a reaction inertsolvent to form a compound of the formula VI. Examples of suitablecoupling reagents which activate the carboxylic functionality aredicyclohexylcarbodiimide, N-3-dimethylaminopropyl-N′-ethylcarbodiimide,2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), carbonyldiimidazole (CDI), and diethylphosphorylcyanide. Suitable bases includedimethylaminopyridine (DMAP), hydroxybenzotriazole (HBT), ortriethylamine, preferably dimethylaminopyridine. The coupling isconducted in an inert solvent, preferably an aprotic solvent. Suitablesolvents include acetonitrile, dichloromethane, dichloroethane, anddimethylformamide. The preferred solvent is dichloromethane. Thetemperature of the aforesaid reaction is generally from about −30 toabout 80° C., preferably about 0 to about 25° C.

The compound of formula VI is converted into a compound of the formulaVII by reaction with acetyl chloride or acetic anhydride in the presenceof a base in a reaction inert solvent. Suitable solvents includemethylene chloride, tetrahydrofuran and chloroform, preferably methylenechloride. Suitable bases include trialkylamines such as triethylamineand tributylamine, dimethylaminopyridine and potassium carbonate,preferably triethylamine. The temperature of the aforesaid reaction isin the range from about 0° C. to about 35° C. for about 1 hour to about10 hours, preferably at about 30° C. for about 3 hours.

The compound of formula VII is cyclized to a compound of formula II byreaction with triphenylphosphine, a base, and a dialkyl azodicarboxylatein a reaction inert solvent. Suitable bases include pyridine,triethylamine and 4-dimethylaminopyridine, preferably4-dimethylaminopyridine. Suitable solvents include dimethylformamide,tetrahydrofuran and dioxane, preferably dioxane. The temperature of theaforesaid reaction is in the range from about 25° C. to about 125° C.for about 1 hour to about 24 hours, preferably at about 100° C. forabout 8 to 15 hours. The compound of formula II can be converted into acompound of formula I according to the method described in Scheme 1.

Compounds of formula II can also be made according to the methodsdescribed in Miyashita, et al., Heterocyclesl 42, 2, 691-699 (1996).

In Scheme 3, the compound of formula 11 is converted to thecorresponding compound of formula VIII by reacting II with a base, aslithium diisopropylamide, in a polar aprotic solvent such astetrahydrofuran. The solution is stirred at a temperature between about−100° C. to about 0° C., preferably about −78° C., for a time periodbetween about 15 minutes to about 1 hour, preferably about 30 minutes.The anionic product so formed is reacted with with a tetrahydrofuransolution of an aldehyde of the formula R²CHO. The solution of aldehydecan be added to the anion solution (normal addition) or the anionsolution can be added to the solution of the aldehyde (inverseaddition). While both methods can be used to produce compounds offormula VII, inverse additional is preferred. The resulting reactionmixture is stirred for a time period between about 15 minutes to about 1hour, preferably about 30 minutes, at a temperature between about −100°C., preferably about −78° C., and then is allowed to warm to ambienttemperature. In reaction 2 of Scheme 3, the compound of formula VIII isconverted to the corresponding compound of formula I by reacting VIIwith a dehydrating agent, such as trifluoroacetic anhydride, in dryreaction inert solvent, such as dioxane, toluene, diglyme ordichloroethane, preferably dioxane. The reaction mixture is stirred at atemperature between about 0° C. to about 50° C., preferably roomtemperature, for a time period between about 1 hour to about 14 hours,preferably about 12 hours.

Compounds of the formula I wherein the dashed line represents a singlecarbon-carbon bond may be prepared by hydrogenating the correspondingcompounds wherein the dashed line represents a double carbon-carbonbond, using standard techniques that are well known to those skilled inthe art. For example, reduction of the double bond may be effected withhydrogen gas (H₂), using catalysts such as palladium on carbon (Pd/C),palladium on barium sulfate (Pd/BaSO₄), platinum on carbon (Pt/C), ortris(triphenylphosphine) rhodium chloride (Wilkinson's catalyst), in anappropriate solvent such as methanol, ethanol, THF, dioxane or ethylacetate, at a pressure from about 1 to about 5 atmospheres and atemperature from about 10° C. to about 60° C., as described in CatalyticHydrogenation in Organic Synthesis, Paul Rylander, Academic Press Inc.,San Diego, 1979, pp. 31-63. The following conditions are preferred: Pdon carbon, ethyl acetate at 25° C. and 15-20 psi of hydrogen gaspressure. This method also provides for introduction of hydrogenisotopes (i.e, deuterium, tritium) by replacing ¹H₂ with ²H₂ or ³H₂ inthe above procedure.

When R² is heteroaryl, one of ordinary skill in the art will understandthat heteroaryl is selected from the group consisting of pyridin-2-yl,1,3-pyrazin-4-yl, 1,4-pyrazin-3-yl, 1,3-pyrazin-2-yl, pyrrol-2-yl,1,3-imidazol-4-yl, 1,3-imidazol-2-yl, 1,3,4-triazol-2-yl,1,3-oxazol-4-yl, 1,3-oxazol-2-yl, 1,3-thiazol-4-yl, 1,3-thiazol-2-yl,1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, fur-2-yl, 1,3-oxazol-5-yl,and 1,3,4-oxadiazol-2-yl, wherein said heteroaryl may optionally besubstituted on any of the atoms capable of forming an additional bond,up to a maximum of three substituents.

Unless indicated otherwise, the pressure of each of the above reactionsis not critical. Generally, the reactions will be conducted at apressure of about one to about three atmospheres, preferably at ambientpressure (about one atmosphere)

The compounds of the formula Ia which are basic in nature are capable offorming a wide variety of different salts with various inorganic andorganic acids. Although such salts must be pharmaceutically acceptablefor administration to animals, it is often desirable in practice toinitially isolate a compound of the formula I from the reaction mixtureas a pharmaceutically unacceptable salt and then simply convert thelatter back to the free base compound by treatment with an alkalinereagent, and subsequently convert the free base to a pharmaceuticallyacceptable acid addition salt. The acid addition salts of the basecompounds of this invention are readily prepared by treating the basecompound with a substantially equivalent amount of the chosen mineral ororganic acid in an aqueous solvent medium or in a suitable organicsolvent such as methanol or ethanol. Upon careful evaporation of thesolvent, the desired solid salt is obtained.

The acids which are used to prepare the pharmaceutically acceptable acidaddition salts of the base compounds of this invention are those whichform non-toxic acid addition salts, i.e., salts containingpharmacologically acceptable anions, such as hydrochloride,hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate oracid phosphate, acetate, lactate, citrate or acid citrate, tartrate orbitartrate, succinate, maleate, fumarate, gluconate, saccharate,benzoate, methanesulfonate and pamoate [i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)] salts.

Those compounds of the formula Ia which are acidic in nature are capableof forming base salts with various pharmacologically acceptable cations.Examples of such salts include the alkali metal or alkaline-earth metalsalts and particular, the sodium and potassium salts. These salts areall prepared by conventional techniques. The chemical bases which areused as reagents to prepare the pharmaceutically acceptable base saltsof this invention are those which form non-toxic base salts with theherein described acidic compounds of formula Ia. These non-toxic basesalts include those derived from such pharmacologically acceptablecations as sodium, potassium, calcium and magnesium, etc. These saltscan easily be prepared by treating the corresponding acidic compoundswith an aqueous solution containing the desired pharmacologicallyacceptable cations, and then evaporating the resulting solution todryness, preferably under reduced pressure. Alternatively, they may alsobe prepared by mixing lower alkanolic solutions of the acidic compoundsand the desired alkali metal alkoxide together, and then evaporating theresulting solution to dryness in the same manner as before. In eithercase, stoichiometric quantities of reagents are preferably employed inorder to ensure completeness of reaction of maximum product of yields ofthe desired final product.

The compounds of the formula Ia and the pharmaceutically acceptablesalts thereof (hereinafter, also referred to as “the active compounds ofthe invention”) are useful for the treatment of neurodegenerative andCNS-trauma related conditions and are potent AMPA receptor agonists andantagonists. The active compounds of the invention may therefore be usedin the treatment or prevention of cerebral deficits subsequent tocardiac bypass surgery and grafting, stroke, cerebral ischemia, spinalcord trauma, head trauma, Alzheimer's Disease, Huntington's Chorea,amyotrophic lateral sclerosis, epilepsy, AIDS-induced dementia,perinatal hypoxia, hypoxia (such as conditions caused by strangulation,surgery, smoke inhalation, asphyxiation, drowning, choking,electrocution or drug or alcohol overdose), cardiac arrest, hypoglycemicneuronal damage, opiate tolerance, addiction withdrawal (such asalcoholism and drug addiction including opiate, cocaine and nicotineaddiction), idiopathic and drug induced Parkinson's Disease and brainedema, and muscular spasms, migraine headaches, urinary incontinence,psychosis, convulsions, chronic or acute pain, ocular damage,retinopathy, retinal neuropathy, tinnitus, anxiety, emesis and tardivedyskinesia.

The in vitro and in vivo activity of the compounds of the invention forAMPA receptor antagonism can be determined by methods available to oneof ordinary skill in the art. One method for determining the activity ofthe compounds of the invention is by inhibition of pentylenetetrazol(PTZ)-induced seizures. Another method for determining the activity ofthe compounds of the invention is by blockage of AMPA receptoractivation-induced ⁴⁵Ca²⁺ uptake.

One specific method for determining inhibition of pentylenetetrazol(PTZ)-induced seizures is as follows. The activity of the compounds ofthe invention for inhibition of pentylenetetrazol (PTZ)-induced seizuresin mice can be determined according to the following procedure. Thisassay examines the ability of compounds to block seizures and deathproduced by PTZ. Measures taken are latency to clonic and tonicseizures, and death. ID₅₀s are determined based on percent protection.

Male CD-1 mice from Charles River, weighing 14-16 g on arrival and 25-35g at the time of testing, serve as subjects for these experiments. Miceare housed 13 per cage under standard laboratory conditions on a L:D/7a.m.: 7 p.m. lighting cycle for at least 7 days prior toexperimentation. Food and water are available ad libitum until the timeof testing.

All compounds are administered in a volume of 10 ml/kg. Drug vehicleswill depend on compound solubility, but screening will typically be doneusing saline, distilled water, or E:D:S/5:5:90 (5% emulphor, 5% DMSO,and 90% saline) as the injection vehicle.

Mice are administered the test compounds or vehicle (i.p., s.c., orp.o.) and are placed into plexiglass cages in groups of five. At apredetermined time after these injections, mice are given an injectionof PTZ (i.p., 120 mg/kg) and placed into individual plexiglass cages.Measures taken during this five minute test period are: (1) latency toclonic seizures, (2) latency to tonic seizures, and (3) latency todeath. Treatment groups are compared to the vehicle-treated group byKruskal-Wallis Anova and Mann-Whitney U tests (Statview). Percentprotection is calculated for each group (number of subjects not showingseizure or death as indicated by a score of 300 secs) at each measure.ID₅₀'s are determined by probit analysis (Biostat).

Another method for determining the activity of the compounds is todetermine the effect of the compounds on motor coordination in mice.This activity can be determined according to the following procedure.

Male CD-1 mice from Charles River, weighing 14-16 g on arrival and 23-35g at the time of testing, serve as subjects for these experiments. Miceare housed 13 per cage under standard laboratory conditions on a L:D/7a.m.: 7 p.m. lighting cycle for at least 7 days prior toexperimentation. Food and water are available ad libitum until the timeof testing.

All compounds are administered in a volume of 10 ml/kg. Drug vehicleswill depend on compound solubility, but screening will typically be doneusing saline, distilled water, or E:D:S/5:5:90 (5% emulphor, 5% DMSO,and 90% saline) as the injection vehicle.

The apparatus used in these studies consists of a group of five13.34×13.34 cm wire mesh squares suspended on 11.43 cm steel polesconnected to a 165.1 cm pole which is elevated 38.1 cm above the labbench. These wire mesh squares can be turned upside-down.

Mice are administered test compounds or vehicle (i.p., s.c., or p.o) andare placed into plexiglass cages in groups of five. At a predeterminedtime after these injections, mice are placed on top of the wire meshsquares and flipped so that they are suspended upside-down. During theone minute test, mice are rated 0 if they fall off the screen, m 1 ifthey hang on upside-down, or 2 if they climb up onto the top. Treatmentgroups are compared to the vehicle-treated group with Kruskal-Wallis andMann-Whitney U tests (Statview).

One specific method for determining AMPA receptor activation-induced⁴⁵Ca²⁺ uptake is described below.

Neuronal Primary Cultures

Primary cultures of rat cerebellar granule neurons are prepared asdescribed by Parks, T. N., Artman, L. D., Alasti, N., and Nemeth, E. F.,Modulation Of N-Methvl-D-Aspartate Receptor-Mediated Increases InCytosolic Calcium In Cultured Rat Cerebellar Granule Cells, Brain Res.552, 13-22 (1991). According to this method, cerebella are removed from8 day old CD rats, minced into 1 mm pieces and incubated for 15 minutesat 37° C. in calcium-magnesium free Tyrode's solution containing 0.1%trypsin. The tissue is then triturated using a fine bore Pasteurpipette. The cell suspension is plated onto poly-D-lysine coated 96-welltissue culture plates at 10⁵ cells per well. Medium consists of MinimalEssential Medium (MEM), with Earle's salts, 10% heat inactivated FetalBovine Serum, 2 mM L-glutamine, 21 mM glucose, Penicillin-Streptomycin(100 units per ml) and 25 mM KCl. After 24 hours, the medium is replacedwith fresh medium containing 10 μM cytosine arabinoside to inhibit celldivision. Cultures should be used at 6-8 DIV.

AMPA Receptor Activation-induced ⁴⁵Ca²⁺ Uptake

The effects of drugs on AMPA receptor activation-induced ⁴⁵Ca²⁺ uptakecan be examined in rat cerebellar granule cell cultures. Cultures in 96well plates are preincubated for approximately 3 hours in serum freemedium and then for 10 minutes in a Mg²⁺-free balanced salt solution (inmM: 120 NaCl, 5 KCl, 0.33 NaH₂PO₄1.8 CaCl₂, 22.0 glucose and 10.0 HEPESat pH 7.4) containing 0.5 mM DTT, 10 uM glycine and drugs at 2× finalconcentration. The reaction is started by rapid addition of an equalvolume of the balanced salt solution containing 100 μM of the AMPAreceptor agonist kainic acid and ⁴⁵Ca²⁺ (final specific activity 250Ci/mmol). After 10 minutes at 25° C., the reaction is stopped byaspirating the ⁴⁵Ca²⁺-containing solution and washing the cells 5× in anice cold balanced salt solution containing no added calcium and 0.5 mMEDTA. Cells are then lysed by overnight incubation in 0.1% Triton-X100and radioactivity in the lysate is then determined. All of the compoundsof the invention, that were tested, had IC₅₀s of less than 500 nM.

The compositions of the present invention may be formulated in aconventional manner using one or more pharmaceutically acceptablecarriers. Thus, the active compounds of the invention may be formulatedfor oral, buccal, transdermal, intranasal, parenteral (e.g.,intravenous, intramuscular or subcutaneous) or rectal administration orin a form suitable for administration by inhalation or insufflation.

For oral administration, the pharmaceutical compositions may take theform of, for example, tablets or capsules prepared by conventional meanswith pharmaceutically acceptable excipients such as binding agents(e.g., pregelatinised maize starch, polyvinylpyrrolidone orhydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystallinecellulose or calcium phosphate); lubricants (e.g., magnesium stearate,talc or silica); disintegrants (e.g., potato starch or sodium starchglycollate); or wetting agents (e.g., sodium lauryl sulphate). Thetablets may be coated by methods well known in the art. Liquidpreparations for oral administration may take the form of, for example,solutions, syrups or suspensions, or they may be presented as a dryproduct for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents (e.g.,sorbitol syrup, methyl cellulose or hydrogenated edible fats);emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles(e.g., almond oil, oily esters or ethyl alcohol); and preservatives(e.g., methyl or propyl p-hydroxybenzoates or sorbic acid).

For buccal administration the composition may take the form of tabletsor lozenges formulated in conventional manner.

For transdermal administration the composition may take the form ofpatches, creams, ointments or iontophoresis formulated in conventionalmanner such as described in U.S. Pat. Nos. 5,004,610 or 5,364,630 issuedApr. 2, 1991 and Nov. 15, 1994 respectively.

The active compounds of the invention may be formulated for parenteraladministration by injection, including using conventionalcatheterization techniques or infusion. Formulations for injection maybe presented in unit dosage form, e.g., in ampules or in multi-dosecontainers, with an added preservative. The compositions may take suchforms as suspensions, solutions or emulsions in oily or aqueousvehicles, and may contain formulating agents such as suspending,stabilizing and/or dispersing agents. Alternatively, the activeingredient may be in powder form for reconstitution with a suitablevehicle, e.g., sterile pyrogen-free water, before use.

The active compounds of the invention may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g., containingconventional suppository bases such as cocoa butter or other glycerides.

For intranasal administration or administration by inhalation, theactive compounds of the invention are conveniently delivered in the formof a solution or suspension from a pump spray container that is squeezedor pumped by the patient or as an aerosol spray presentation from apressurized container or a nebulizer, with the use of a suitablepropellant, e.g, dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. The pressurized containeror nebulizer may contain a solution or suspension of the activecompound. Capsules and cartridges (made, for example, from gelatin) foruse in an inhaler or insufflator may be formulated containing a powdermix of a compound of the invention and a suitable powder base such aslactose or starch.

A proposed dose of the active compounds of the invention for oral,parenteral or buccal administration to the average adult human for thetreatment of the conditions referred to above (e.g., stroke) is 0.01 to20 mg/kg of the active ingredient per unit dose which could beadministered, for example, 1 to 4 times per day.

Aerosol formulations for treatment of the conditions referred to above(e.g., stroke) in the average adult human are preferably arranged sothat each metered dose or “puff” of aerosol contains 20 μg to 1000 μg ofthe compound of the invention. The overall daily dose with an aerosolwill be within the range 100 μg to 10 mg. Administration may be severaltimes daily, for example 2, 3, 4 or 8 times, giving for example, 1, 2 or3 doses each time.

The following Examples illustrate the preparation of the compounds ofthe present invention. Commercial reagents were utilized without furtherpurification. Melting points are uncorrected. All NMR data were recordedat 250, 300 or 400 MHz in deuterochloroform unless otherwise specifiedand are reported in parts per million (δ) and are referenced to thedeuterium lock signal from the sample solvent. All non-aqueous reactionswere carried out in dry glassware with dry solvents under an inertatmosphere for convenience and to maximize yields. All reactions werestirred with a magnetic stirring bar unless otherwise stated. Unlessotherwise stated, all mass spectrum were performed using chemical impactconditions. Ambient or room temperature refers to 20-25° C.

EXAMPLE 1(S)-6-Fluoro-3-(2-methyl-pyridin-3-yl)-2-[2-(2-methyl-thiazol-4-yl)-vinyl]-3H-quinazolin-4-oneMesylate and(R)-6-fluoro-3-(2-methyl-pyridin-3-yl)-2-[2-(2-methyl-thiazol-4-yl)-vinyl]-3H-quinazolin-4-oneMesylate

Racemic-fluoro-3-(2-methyl-pyridin-3-yl)-2-[2-(2-methyl-thiazol-4-yl)-vinyl]-3H-quinazolin-4-one(0.090 g) was dissolved in 0.1% diethylamine/isopropanol (60 mL) (finalconcentration 1.5 mg/mL) and applied to a preparative HPLC column (5×50cm Chiralcel AD) and eluted with 85/15/0.1heptane/isopropanol/diethylamine at a flow rate of 100 ml/min. Theeluent was monitored with ultraviolet detection at 265 nM. Two fractionswere collected, the first component centered around an elution time of60 min and the second around an elution time of 75 min. The total cycletime for the run was 90 min. The eluent from 4 cycles with elution timeof 60 min were combined and concentrated to give an oily tan solid. Thesolid was triturated with ether/hexane to afford 0.175 g of tan powder.This powder was nearly dissolved in magnetically stirred ethyl acetate(15 mL) and treated with 1 N methanesulfonic acid in ethyl acetate(0.462 mL, 0.462 mmol). A salt immediately began precipitating. Themixture was stirred for 6 hours, at which time the product wascollected, rinsed with ethyl acetate, and dried to afford 0.144 g of(+)-6-fluoro-3-(2-methyl-pyridin-3-yl)-2-[2-(2-methyl-thiazol-4-yl)-vinyl]-3H-quinazolin-4-onemesylate as a light yellow solid.

Melting point 145-146° C. (The melted material equilibrated andresolidified. Continued heating resulted in a second melting range of210-225° C.) The product also had: NMR (methanol_(d4)) δ 9.02 (dd,J=1.5, 6 Hz, 1H), 8.69 (dd, J=1.5, 8.3 Hz, 1H), 8.17 (dd, J=6, 8.2 Hz,1H), 8.01 (d, J=15 Hz, 1H), 7.92-7.85 (m, 2H), 7.76 (s,1H), 7.72 (dt,J=3, 8.7 Hz, 1H), 6.58 (d, J=15 Hz, 1H), 2.68 (s, 3H), 2.67 (s, 3H),2.63 (s, 3H); [α]^(D)=+18.9° (c=0.18 in methanol).

The eluent from the same four cycles with elution time of 75 min wereconcentrated and converted to mesylate salt in the same fashion toafford 0.144 g of(−)-6-fluoro-3-(2-methyl-pyridin-3-yl)-2-[2-(2-methyl-thiazol-4-yl)-vinyl]-3H-quinazolin-4-onemesylate as a light yellow solid which had: [α]^(D)=−18.3° (c=0.175 inmethanol). All other physical characteristics were identical to theatropisomer.

EXAMPLES 2-7

Examples 2-7 were prepared according to methods analogous to those ofExample 1.

TABLE 1 Column; Retention Exam- Mobile Phase; UV Time ple Name Flow rate(nm) (minutes) 2 6-Fluoro-3-(2-methyl- Chiralpak AD; 360 6.825pyridin-3-yl)-2-[2-(4- 70/30 hexane/ methyl-thiazol-2-yl)- isopropanol +vinyl]-3H-quinazolin-4-one 0.1 diethyl amine; 1 mL/min 36-Fluoro-3-(2-methyl- Chiralpak AD; 360 9.674 pyridin-3-yl)-2-[2-(4-70/30 hexane/ methyl-thiazol-2-yl)- isopropanol +vinyl]-3H-quinazolin-4-one 0.1 diethyl amine 1 mL/min 42-{2-[6-Fluoro-3-(2- Chiralpak AD; 335 9.861 methylpyridin- 3-yl)-4-oxo-70/30 hexane/ 3,4-dihydroquinazolin- 2- isopropanol +yl]-vinyl}-benzonitrile 0.1 diethyl amine; 1 mL/min 52-{2-[6-Fluoro-3-(2- Chiralpak AD; 335 13.951 methylpyridin-3-yl)-4-oxo- 70/30 hexane/ 3,4-dihydroquinazolin- 2- isopropanol +yl]-vinyl}-benzonitrile 0.1 diethyl amine; 1 mL/min 6 2-{2-[3-(2-Chloro-Chiralpak AD; 335 11.372 pyridin-3-yl)-6-fluoro- 70/30 hexane/4-oxo-3,4-dihydroquinazol- isopropanol + in-2-yl]-vinyl}-benzonitrile0.1 diethyl amine; 1 mL/min 7 2-{2-[3-(2-Chloro- Chiralpak AD; 33520.264 pyridin-3-yl)-6-fluoro- 70/30 hexane/ 4-oxo-3,4-dihydroquinazol-isopropanol + in-2-yl]-vinyl}-benzonitrile 0.1 diethyl amine; 1 mL/min

EXAMPLES 8-9

All HPLC analytical separation experimental conditions described belowwere carried out with a Hewlett Packard model 1050 HPLC. The dimensionsof the analytical columns were 4.6 mm×25 cm and the stationary phaseparticle size was 10 micron. All samples were dissolved in methanol.

(S)-3-(2-Chloro-pyridin-3-yl)-6-fluoro-2-[2-(fluoro-phenyl)-vinyl]-3H-quinazolin-4-one

Column Chiralcel OD Mobile Phase 80/20 hexane/isopropyl alcohol with0.1% diethylamine Flow Rate 1 mL/min Detection UV (250 nM) RetentionTime (first atropisomer) 18.697 min Retention Time (second atropisomer)22.102 min

(S)-6-Fluoro-3-(2-methyl-pyridin-3-yl)-2-[2-(2-methyl-thiazol-4-yl)-vinyl]-3H-quinazolin-4-one

Column Chiralcel OD Mobile Phase 90/10 hexane/isopropyl alcohol with0.1% diethylamine Flow Rate 1 mL/min Detection UV (250 nM) RetentionTime (first atropisomer) 38.038 min Retention Time (second atropisomer)45.032 min

PREPARATION 13-(2-Chlorophenyl)-2-[2-(6-diethylaminomethylpyridin-2-yl)-vinyl]-6-fluoro-3H-quinozolin-4-oneMethod A 6-Fluoro-2-methylquinoxalin-4-one

A solution of 12.95 g (70.0 mmol) of 2-nitro-5-fluorobenzoic acid in 200mL of glacial acetic acid and 20 mL of acetic anhydride was treated with0.625 g of 10% palladium on carbon are reduced at an initial pressure of54.5 psi. Hydrogen uptake was complete after two hours. The catalyst wasremoved by filtration and the filtrate was heated at reflux for twohours at which time TLC (1:1 hexane/ethyl acetate) indicated that thereaction was complete. The reaction mixture was evaporated to asemicrystalline mass which was broken up in a minimum amount of2-propanol and stirred in an ice bath for one hour. The crystallinesolid was separated by filtration, washed with minimal cold 2-propanoland air dried to give 5.79 g (46%) of the desired product as a brownsolid, m.p. 127.5-128.5° C.

A synthesis of 5-fluoro-2-nitrobenzoic acid is described by Slothouwer,J. H., Recl. Trav. Chim. Pays-Bas 33, 336 (1914).

Method B 3-(2-Chlorophenyl)-6-fluoro-2-methyl-4-(3H)-guinazolinone

A solution of 2.50 g (14.0 mmol) of 6-fluoro-2-methylquinoxalin-4-oneand 1.96 g (15.4 mmol) of 2-chloroaniline in about 20 mL of glacialacetic acid was heated at reflux under a nitrogen atmosphere for 6hours. Most of the solvent was evaporated from the cooled reactionmixture and the residues were taken up in ethanol and refrigerated.After 6 days in the refrigerator, the formed crystals were filtered off,washed with minimal cold ethanol and air dried to give 1.79 g (44%) ofthe product. m.p. 137-138° C.

Method C6-(2-[3-(2-Chlorophenyl)-6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl-vinyl)pyridine-2-carbaldehyde

A catalytic amount (about 100 mg) of anhydrous zinc chloride was addedto a solution of 576 mg (2.0 mmol) of3-(2-chlorophenyl)-6-fluoro-2-methyl-4(3H)-quinazolinone and 270 mg (2.0mmol) of 2,6-pyridinedicarboxaldehyde in 20-25 mL of dioxane and 1.0 mLof acetic anhydride. The reaction mixture was heated at reflux under anitrogen atmosphere for 3 hours until TLC indicated that the startingmaterials had been consumed. The cooled reaction mixture was poured intowater and the mixture was extracted with ethyl acetate. The combinedextracts were dried with brine and magnesium sulfate, treated withdecolonizing carbon and filtered and the solvent was removed to give thedesired product. This was taken up in 2:1 ether/pentane and the crystalswere filtered to give 266 mg of the product, 33%, m.p. 247-248° C.

A synthesis of pyridine-2,6-dicarboxaldehyde is described byPapadopoulos, et. al., J. Org. Chem. 31, 615 (1966).

Method D3-(2-Chlorophenyl)-2-[2-(6-diethylaminomethylpyridin-2-yl)-vinyl]-6-fluoro-3H-quinozolin-4-one

A solution of 65 mg (0.16 mmol) of6-{2-[3-(2-chlorophenyl)-6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-vinyl)pyridine-2-carbaldehydein 10 mL of methylene chloride at room temperature under a nitrogenatmosphere was treated with 3 drops of diethylamine and 73 mg (0.34mmol) of sodium triacetoxyborohydride. After stirring for 2 ½ hour atroom temperature, the solvent was evaporated and the residues werepartitioned between dilute hydrochloric acid and either and stirred for30 minutes. The ethereal layer was separated and the aqueous wasextracted once again with ether the ethereal extracts were discarded.The aqueous acidic solution was adjusted to a pH of about 14 with 10%sodium hydroxide (ice bath cooling) and was then extracted with ethertwice. The combined ethereal extracted were dried with brine and withmagnesium sulfate and the solvent was evaporated. After one attempt toform a mesylate salt, the reworked free base in ethyl acetate wastreated with 7.5 mg (0.06 mmol) of maleic acid dissolved in a littleethyl acetate. Crystals formed from the resulting solutions which werefiltered and washed with ethyl acetate to give 22 mg of the monomaleatesalt, (24%), m.p. 170.5-171.5° C.

PREPARATION 2-19

Preparations 2-19 were made according to methods analogous to those ofPreparation 1.

TABLE 1

Prep R³ 2 3 4 NMR 2 H Cl F H (CDCl₃) δ6.38(1H, d, J=13), 7.00- 7.11(2H,m), 7.25-7.34(2H, m), 7.46- 7.52(2H, m), 7.77-7.84(3H, m), 8.10(1H, d,J=13), 8.29(1H, d, J=6), 8.61(1H, m). 3 F Cl F H (CDCl₃) δ6.36(1H, d,J=13), 7.00- 7.12(2H, m), 7.25-7.33(2H, m), 7.49- 7.58(2H, m),7.76-7.86(2H, m), 7.91-7.94(1H, d, J=6), 8.08(1H, d, J=13), 8.61(1H, m).4 F CH₃ F H (CDCl₃) δ2.37(3H, s), 6.35(1H, d, J=13), 7.00-7.10(2H, m);7.25-7.32 (2H, m), 7.37-7.41(1H, m), 7.51- 7.58(2H, m), 7.81-7.85(1H,m), 7.91- 7.94(1H, d, J=6), 8.06(1H, d, J=13), 8.71(1H, m). 5 F Cl H

(CDCl₃) δ1.00(6H, t, J=6), 1.98(4H, q, J=6), 3.50(2H, s), 6.29(1H, d,J=13), 7.16-7.66(6H, m), 7.72-7.85 (2H, m), 7.92(1H, d, J=6), 8.03(1H,d, J=13), 8.62(1H, m). 6 F Cl H CHO (CDCl₃) δ6.29(1H, d, J=13), 7.47-7.62(4H, m), 7.68-7.96(5H, m), 8.07 (1H, d, J=13), 8.63(1H, m), 9.98(1H,s). 7 H Cl H CHO (CDCl₃) δ6.31(1H, d, J=13), 7.48- 7.61(5H, m),7.78-7.84(4H, m), 8.10 (1H, d, J=13), 8.30(1H, d, J=6), 8.63 (1H, m),10.00(1H, s). 8 F Cl H

(CDCl₃) δ4.66(2H, s), 6.20(1H, d, J=13), 7.22-7.32(5H, m), 7.50-7.58(2H, m), 7.75-7.83(2H, m), 7.90- 7.93(1H, m), 8.02(1H, m, J=13), 8.61(1H, m). 9 F Cl CN H (CDCl₃) δ6.50(1H, d, J=13), 7.39- 7.68(6H, m),7.78-7.95(3H, m), 8.25 (1H, d, J=13), 8.62(1H, m). 10 F Cl H

(CDCl₃) δ1.72(4H, broad t), 2.50(4H, broad t), 3.49(2H, s), 3.96(4H, s),6.21(1H, d, J=13), 7.22-7.35(4H, m), 7.51-7.58(2H, m), 7.77-7.84 (2H,m), 7.90-7.94(1H, m), 8.03 (1H, d, J=13), 8.64(1H, m). 11 F Cl H

(CDCl₃) δ1.47-1.61(1H, m), 1.73- 2.10(12H, m), 2.50-2.60(3H, m),2.77-2.88(1H, m), 3.43(2H, s), 6.70 (1H, d, J=13), 7.18-7.33(4H, m),7.50-7.61(2H, m), 7.74-7.83(2H, m), 7.89-7.96(1H, m), 8.01(1H, d, J=13),8.67(1H, m). 12 H Cl CN H (CDCl₃) δ6.52(1H, d, J=13), 7.38- 7.86(9H, m),8.27(1H, d, J=13), 8.30 (1H, s), 8.61(1H, m). 13 H CH₃ CN H (CDCl₃)δ2.39(3H, s), 6.47(1H, d, J=13), 7.35-7.42(3H, m), 7.49-7.60 (3H, m),7.64-7.67(1H, m), 7.76- 7.86(2H, m), 8.29(1H, m), 8.31(1H, d, J=13),8.70(1H, m). 14 H CH₃ F H (CDCl₃) δ2.38(3H, s), 6.38(1H, d, J=10),7.00-7.10(2H, m), 7.25-7.32 (2H, m), 7.36-7.40(1H, m), 7.47- 7.58(2H,m), 8.812H, s), 8.11(1H, d, J=10), 8.31(1H, J=6), 8.70(1H, m). 15 F ClOH H (CDCl₃/DMSO-d₆) δ6.34(1H, d, J=10), 6.55-6.68(2H, m), 6.91-7.02(2H,m), 7.32-7.39(2H, m), 7.61-7.79 (3H, m), 8.00(1H, d, J=10), 8.41(1H, m).16 F CH₃ CN H (CDCl₃) δ2.39(3H, s), 6.45(1H, d, J=10), 7.37-7.43(3H, m),7.49-7.60 (3H, m), 7.67(1H, d, J=6), 7.85-7.96 (2H, m), 8.28(1H, d,J=10), 8.72(1H, m). 17 Cl CH₃ F H (CDCl₃) δ2.38(3H, s), 6.37(1H, d,J=15), 7.01-7.12(2H, m), 7.24-7.34 (2H, m), 7.35(1H, m), 7.57(1H, d,J=6), 7.76(2H, m), 8.12(1H, d, J=15), 8.26(1H, s), 8.73(1H, m).

PREPARATION 18

NMR: (CDCl₃) δ 2.44 (3H, s), 6.83 (1H, D, J=13), 7.04 (1H, d, J=10),7.13 (1H, d, J=10), 7.50-7.58 (3H, m), 7.78-7.84 (2H, m), 7.92 (1H, m),7.96 (1H, d, J=10), 8.61 (1H, m).

PREPARATION 19

NMR: (CDCl₃) δ 2.09 (3H, s), 6.45 (1H, d, J=15), 7.03-7.18 (3H, m),7.31-7.40 (2H, m), 7.75 (2H, s), 8.14 (1H, d, J=15), 8.22-8.71 (3H, m).

PREPARATION 206-Fluoro-3-(2-methyl-pyridin-3-yl)-2-[2-(2-methyl-thiazol-4-yl)-vinyl]-3H-quinazolin-4-oneand its Mesylate Salt

Anhydrous zinc chloride (2.7 g, 20 mmol) was fused with a nitrogen purgein a round bottom flask with an open flame. The reaction vessel wasallowed to return to ambient temperature, then dioxane (150 mL) wasadded. To this mixture was added6-fluoro-2-methyl-3-(2-methyl-pyridin-3-yl)-3H-quinazolin-4-one (2.6 g,10 mmol), acetic anhydride (2.8 mL, 30 mmol), and2-methylthiazole-4-carboxaldehyde (3.7 g, 30 mmol). The reaction wasrefluxed for 2 hours, then cooled to ambient temperature, and dilutedwith water. Sodium carbonate was added until the mixture was basic. Oncethe mixture was basic it was repeatedly extracted with chloroform. Thecombined chloroform layers were washed with water and brine and finallydried over sodium sulfate and concentrated to leave a dark residue. Thisresidue was treated with methanol and concentrated (effectivelyazeotroping any residual chloroform from the residue). This process wasrepeated until a brown solid was formed. The solid was triturated withether (twice), filtered and dried to afford 3.1 g (82%) of6-fluoro-3-(2-methyl-pyridin-3-yl)-2-[2-(2-methyl-thiazo-4-yl)-vinyl]-3H-quinazolin-4-oneas tan solid.

Melting Point: 223-224° C. NMR δ 8.70 (dd, J=1.5, 5 Hz, 1H), 7.90 (ddpartially obscurred, J=3 Hz, 1H), 7.89 (d, J=15 Hz, 1H), 7.78 (dd, J=5,9 Hz, 1 H), 7.54 (m, 2H), 7.39 (dd, J=5, 8 Hz, 1H), 7.23 (s, 1H), 6.57(d, J=15 Hz, 1 H), 2.61 (s, 3H), 2.36 (s, 3H). Analysis calculated forC₂₀H₁₅FN₄OS 0.5 H₂O: C, 62.06; H, 4.13; N, 14.58. Found: C, 62.39; H,3.96; N, 14.33.

A sample was dissolved in ethyl acetate and treated with 1 Nmethanesulfonic acid in ethyl acetate to form the mesylate salt. Theprecipitate was collected, rinsed with ethyl acetate and dried to afford6-fluoro-3-(2-methyl-pyridin-3-yl)-2-[2-(2-methyl-thiazol-4-yl)-vinyl]-3H-quinazolin-4-onemesylate as a light yellow solid.

Melting point: 230-231° C. NMR (methanol_(d4)) δ 9.01 (dd, J=1.2, 5.8Hz, 1H), 8.65 (dd, J=1.3, 8.2 Hz, 1H), 8.15 (dd, J=5.9, 8.2 Hz, 1H),8.00 (d, J=15 Hz, 1H), 7.88 (sym m, 2H), 7.71 (m, 2H), 6.56 (d, J=15 Hz,1H), 2.68 (s, 3H), 2.65 (s, 3H), 2.62 (s, 3H). Analysis calculated forC₂₀H₁₅FN₄OS CH₃SO₃H 0.75 H₂O: C, 51.69; H, 4.20; N, 11.48. Found: C,51.80; H, 4.18; N, 11.35.

PREPARATION 21

The compounds in table 1 were made by essentially the same procedures asexemplified by preparation 64.

Prep R³ R² R¹ Physical Data 21 F 2-dimethylamino- 2-chloropyrid-3-yl NMRδ8.69(br d, J=4.3 methylthiazol-4-yl Hz, 1H), 7.92(m, 2H), 7.78 (m, 2H),7.54(m, 3H), 6.58 (d, J=14.7Hz, 1H), 4.34 (br s, 2H), 2.74(br s, 6H). 22F 2-dimethylamino- 2-methylpyrid-3-yl NMR δ8.67(d, J=4.7Hz,methylthiazol-4-yl 1H), 7.90(d, J=15Hz, 1H), 7.89(m, 1H), 7.76(dd, J= 5,9Hz, 1H), 7.51(m, 2H), 7.36(m, 1H), 7.34(s, 1H), 6.55(d, J=15Hz, 1H),3.70(s, 2H), 2.34(s, 9H). 23 F 2-methyloxazol-4- 2-methylpyrid-3-yl mp223° C. yl NMR δ8.69(d, J=3.5Hz, 1H), 7.89(dd, J=3, 8.3Hz, 1H), 7.79(d,J=15Hz, 1H), 7.76(dd, J=5, 9Hz, 1H), 7.64(s, 1H), 7.53(m, 2H), 7.38(m,1H), 6.41(d, J= 15Hz, 1H), 2.37(s, 3H), 2.35(s, 3H). 24 F thiazol-2-yl2-chloropyrid-3-yl mp 195° C. NMR δ8.61(dd, J=1.7, 5Hz, 1H), 8.10(d,J=15Hz, 1H), 7.92(dd, J=3, 8.2Hz, 1H), 7.82-7.72(m, 3H), 7.57-7.49(m,2H), 7.37(d, J=3.4Hz, 1H), 6.64(d, J= 15Hz, 1H). 25 F thiazol-2-yl2-methylpyrid-3-yl mp 176° C. NMR δ8.70(dd, J=1.7, 4.7Hz, 1H), 8.09(d,J= 15Hz, 1H), 7.91(dd, J=3, 8.3Hz, 1H), 7.89-7.78(m, 2H), 7.55(m, 2H),7.38-7.34(m, 2H), 6.62(d, J=15Hz, 1H), 2.35(s, 3H). 26 F4-methylthiazol-2- 2-methylpyrid-3-yl mp 178-180° C. yl NMR δ8.70(d,J=4Hz, 1H), 8.04(d, J=15Hz, 1H), 7.91(br d, J=8Hz, 1H), 7.79(dd, J=5,8.7Hz, 1H), 7.55-7.53(m, 2H), 7.40-7.37 (m, 1H), 6.91(s, 1H), 6.55 (d,J=15Hz, 1H), 2.40(s, 3H), 2.36(s, 3H).

PREPARATION 27 2-Dimethylaminomethylthiazole-4-carboxaldehyde

To a slurry of 2-dimethylaminothioacetamide hydrochloride (7.7 g, 50mmol) in ethanol (100 mL) was added ethyl bromopyruvate (6.3 mL). Themixture was refluxed 6 h and then cooled to room temperature. More ethylbromopyruvate (3.2 mL for a total of 75 mmol) was added and the reactionwas refluxed 2.5 h more. The mixture was cooled to ambient temperatureand concentrated at reduced pressure. The residue was partitionedbetween water and ethyl acetate and brought to pH 10 with addition ofsolid potassium carbonate. The phases were separated and the aqueouslayer was extracted with ethyl acetate. The combined organic phase waswashed with water and brine, then it was dried over sodium sulfate andconcentrated to afford an amber oil. This oil was purified by flashchromatography on silica gel (120 g). Elution proceeded as follows: 2%methanol/chloroform, 200 mL, forerun; 10% methanol/chloroform, 75 mL,nil; 750 mL, 10.7 g (100%) of ethyl2-dimethylaminomethylthiazole-4-carboxylate as a clear yellow oil whichhad: NMR δ 8.07 (d, J=1.4 Hz, 1H), 4.32 (q, J=7 Hz, 2H), 3.73 (s, 2H),2.28 (s, 6H), 1.31 (t, J=7 Hz, 3H). The material was suitable for usewithout further purification.

To a mixture of lithium aluminum hydride (4.5 g, 119 mmol) in ice coldtetrahydrofuran (100 mL) was added ethyl2-dimethylaminomethylthiazole-4-carboxylate (8.5 g, 39.7 mmol in 40 mLof tetrahydrofuran) dropwise over 40 min maintaining an internaltemperature of 5-10° C. The mixture was stirred at this temperaturerange for 90 min. The reaction was carefully quenched with saturatedaqueous ammonium chloride (30 mL). The resulting gray slurry was stirred15 min and filtered through celite. The pad was well washed with ethylacetate. The filtrate was washed with brine and dried over sodiumsulfate. Concentration of this organic solution gave 4.2 g (62%) of2-dimethylaminomethyl-4-hydroxymethylthiazole as an amber oil which hadNMR δ 7.12 (s, 1H), 4.71 (s, 2H), 3.73 (s, 2H), 2.50 (br s, 1H), 2.32(s, 6H). The material was used without further purification.

A solution of 2-dimethylaminomethyl-4-hydroxymethylthiazole (4.2 g, 27.3mmol) in methylene chloride (200 mL) was treated with Dess-Martinreagent (14.5 g, 34.1 mmol). The mixture was stirred at ambienttemperature 24 h. Additional Dess-Martin reagent (2.9 g) was added andthe mixture was stirred 4 h more. The reaction was quenched by additionof saturated aqueous sodium thiosulfate (100 mL) and the pH of theresulting mixture was adjusted to 10 by addition of solid potassiumcarbonate. The two phase mixture was filtered. The phases were separatedfrom the filtrate and the aqueous layer was extracted with methylenechloride. The combined organic layer was washed with brine, dried oversodium sulfate, and concentrated to afford a yellow solid. This solidwas purified by flash chromatography on silica gel (50×130 mm) elutingfirst with chloroform (200 mL) and then 2% methanol/chloroformcollecting 25 mL fractions. Fractions 51-80 were combined andconcentrated to leave 2.9 g of a milky yellow oil. This oil wastriturated with 50% ethereal chloroform and a solid was removed byfiltration. The filtrate was concentrated to yield 2.6 g (62%) of2-dimethylaminomethylthiazole-4-carboxaldehyde as a yellow oil whichhad: NMR δ 9.95 (s, 1H), 8.14 (s, 1H), 3.81 (s, 2H), 2.36 (s, 6H). Thisproduct was used without further purification.

PREPARATION 28 2-Methyloxazole-4-carboxaldehyde

Ethyl 2-methyloxaxoline-4-carboxylate was prepared according to thepublished procedure (Heterocycles 1976, 4, 1688).

To an ambient temperature solution of ethyl2-methyloxaxoline-4-carboxylate (6.28 g, 40 mmol) in benzene (300 mL)was added copper (I) bromide (6.31 g, 44 mmol) and then copper (II)acetate (7.99 g, 44 mmol). To this mixture was added tertiary butylperbenzoate (11.4 mL, 60 mmol) dropwise over 15 min and the reactionwarmed slightly to the touch. The black mixture was refluxed 24 h,cooled to ambient temperature and filtered through a celite pad (etherrinse). The filtrate was washed with aqueous ammonium chloride, waterand brine, then it was dried over sodium sulfate and concentrated. Thetan residue was purified by flash chromatography on silica gel (80 g)eluting with 40% ethyl acetate/hexane. After a 100 mL forerun, 20 mLfractions were collected. Fractions 11-22 were collected andconcentrated to afford 4.27 g (69%) of ethyl2-methyloxazole-4-carboxylate as a yellow oil which had: NMR d 8.04 (s,1H), 4.32 (q, J=7 Hz, 2H), 2.46 (s, 3H), 1.33 (t, J=7 Hz, 3H). Thismaterial was used without further purification.

A solution of ethyl 2-methyloxazole-4-carboxylate (0.31 g, 2.0 mmol) intetrahydrofuran (5 mL) was chilled to −65° C. and diisobutylaluminumhydride (4.1 mL of a 1 N solution in toluene, 4.1 mmol) was addeddropwise over 15 min. The solution was allowed to warm to ambienttemperature and stir 15 min. The reaction was chilled to 5° C. andcarefully quenched by addition of methanol (2 mL). The reaction mixturewas returned to ambient temperature and water (0.18 mL) was addedfollowed by sodium fluoride 1.68 g). This mixture was stirred 30 min,then dried with magnesium sulfate and filtered. The filtrate wasconcentrated and azeotroped with chloroform to afford 0.215 g (96%) of4-hydroxymethyl-2-methyloxazole as a pale oil which had: NMR δ 7.45 (s,1H), 4.52 (d, J=6 Hz, 2H), 3.41 (br s, 1H), 2.42 (s, 3H).

A solution of 4-hydroxymethyl-2-methyloxazole (0.79 g, 6.99 mmol) inmethylene chloride (25 mL) was treated with Dess-Martin reagent (8.9 g,20.97 mmol) and stirred 24 h. The reaction was quenched by addition ofsaturated aqueous sodium thiosulfate and stirred 30 min. The mixture wasfiltered. The filtrate was repeatedly extracted with methylene chloride.The combined organic layer was washed with saturated aqueous bicarbonate(twice), water and brine. The organic phase was dried over sodiumsulfate and concentrated to a oily white solid. This residue wastriturated with ether and filtered. The filtrate was concentrated toafford 0.541 g (69%) of 2-methyloxazole-4-carboxaldehyde as a lightyellow solid which had: NMR d 9.88 (s, 1H), 8.15 (s, 1H), 2.52 (s, 3H).

PREPARATION 29

The compounds in table 1 were made by essentially the same procedures asexemplified by Preparation 28.

Prep IUPAC Name NMR 29 3-(2-Chloro-pyridin-3-yl)-6-fluoro-2- (CDCI₃+DMSO−d6) δ5.99 [2-(2-hydroxy-phenyl)-vinyl]-3H- (1H, d, J=15), 6.16-6.24quinazolin-4-one (1H, m), 6.38(1H, d, J=10), 6.42-6.66(2H, m), 6.93-7.12(2H, m), 7.23-7.45 (3H, m), 7.60(1H, d, J=15), 8.04(1H, m), 9.23(1H,broad s). 30 2{2-[6-Fluoro-3-(2-methyl-pyridin- (CDCI₃+DMSO−d6) δ2.033-yl)-4-oxo-3,4-dihydro- (3H, s), 2.07(3H, s), 6.15quinazolin-2-yl]-vinyl}-4-methyl- (1H, d, J=15), 6.82-6.94 benzonitrile(2H, m), 7.11-7.60(7H, m), 7.91(1H, d, J=15), 8.41 (1H, m). 312-[2-(5-Diethylaminomethyl-2- (CDCI₃+DMSO−d6) δ1.72fluoro-phenyl)-vinyl]-6-fluoro-3-(2- (6H, broadened t), 2.76methyl-pyridin-3-yl)-3H-quinazolin- (3H, s), 2.67(2H, broad q), 4-one3.05(2H, broad q), 3.96 (2H, m), 6.40(d, J=15), 6.69-6.78(1H, m), 7.13-7.31(2H, m), 7.48-7.58 (2H, m), 7.72-7.80(1H, m), 7.88(1H, d, J=15),8.05-8.16(2H, m), 8.44 (1H, m). 32 6-Fluoro-2-[2-(2-fluoro-5-pyrrolidin-(CDCI₃+DMSO−d6) δ1.72 1-ylmethyl-phenyl)-vinyl]-3- (4H, broadened s),2.38 (2-methyl-pyridin-3-yl)-3H- (3H, s), 2.64(2H, m), 3.07quinazolin-4-one (2H, m), 3.95(2H, m), 6.40 (1H, d, J=15), 6.71-6.80(2H, m), 7.15-7.32(2H, m), 7.49-7.59 (3H, m), 7.74-7.82(2H, m), 7.90(1H, d, J=15), 8.07-8.17 (2H, m), 8.47(1H, m). 336-Fluoro-2-[2-(2-fluoro-5-pyrrolidin- (CDCI₃+DMSO−d6) δ1.721-ylmethyl-phenyl)-vinyl]-3- (6H, broadened t), 2.76(2-methyl-pyridin-3-yl)-3H- (3H, s), 2.67(2H, broad q), quinazolin-4-one3.05(2H, broad q), 3.96 (2H, m), 6.40(d, J=15), 6.69-6.78(1H, m), 7.13-7.31(2H, m), 7.48-7.58 (2H, m), 7.72-7.80(1H, m), 7.88(1H, d, J=15),8.05-8.16(2H, m), 8.44 (1H, m).

PREPARATION 346-Fluoro-3-(2-methyl-pyridin-3-yl)-2-[2-(2-methyl-thiazol-4-yl)-ethyl]-3H-quinazolin-4-one

To a slurry of 10% palladium on carbon (0.15 g) in methanol(12 mL) wereadded6-fluoro-3-(2-methyl-pyridin-3-yl)-2-[2-(2-methyl-thiazol-4-yl)-vinyl]-3H-quinazolin-4-one (0.075 g, 0.198 mmol) and ammonium formate (1.2 g, 19mmol). The mixture was refluxed overnight, cooled and filtered throughcelite. The pad was washed with methanol. The filtrate was concentrated.The residue was partitioned between chloroform and water. The phaseswere separated and the aqueous layer was extracted with chloroform. Thecombined organic phase was washed with water and brine, dried overmagnesium sulfate, and concentrated to afford 0.035 g (47%) of6-fluoro-3-(2-methyl-pyridin-3-yl)-2-[2-(2-methyl-thiazol-4-yl)-ethyl]-3H-quinazolin-4-oneas a white solid.

Melting point 151-153° C.; NMR δ 8.62 (dd, J=1.5, 5 Hz, 1h), 7.86 (dd,J=3, 8.5 Hz, 1H), 7.73 (dd, J=5, 9 Hz, 1H), 7.49 (dt, J=3, 8 Hz, 1h),7.41 (dd, J=1.5, 8 Hz, 1H), 7.30 (dd, J=5, 8Hz, 1H), 6.70(s,1H), 3.19(sym m, 2H), 2.67 (m, 2H), 2.59 (s, 3H), 2.28 (s, 3H).

What is claimed is:
 1. An atropisomer of the formula

wherein each of “A, B and D” is nitrogen or —CH—, with the proviso thatonly one of “A”, “B” and “D” can be nitrogen; wherein n is an integerfrom one to four and wherein each R⁵ is a substituent on any carbon atomof the “A, B, D” ring capable of supporting an additional bond, with theproviso that one R⁵ must be attached to a carbon atom ortho to theasterisked carbon of the ring; wherein each R⁵ may be independentlyselected from the group consisting of (C₁-C₆)alkyl and halogen; R² is aphenyl group of the formula:

R³ is hydrogen or halo; R⁹ is hydrogen, halo, CF₃, (C₁-C₆)alkyloptionally substituted with one to three halogen atoms, (C₁-C₆)alkoxyoptionally substituted with one to three halogen atoms,(C₁-C₆)alkylthiol, amino-(CH₂)_(s)—, (C₁-C₆)alkyl-NH—(CH₂)_(s)—,di(C₁-C₆)alkyl-N—(CH₂)_(s)—, (C₃-C₇)cycloalkyl-NH—(CH₂)_(s)—,H₂N—(C═O)—(CH₂)_(s)—, (C₁-C₆)alkyl-HN—(C═O)—(CH₂)_(s)—,di(C₁-C₆)alkyl-N—(C═O)—(CH₂)_(s)—,(C₃-C₇)cycloalkyl-NH—(C═O)—(CH₂)_(s)—, R¹³O—(CH₂)_(s)—,R¹³O—(C═O)—(CH₂)_(s)—, H(O═C)—NH—(CH₂)_(s)—,(C₁-C₆)alkyl-(O═C)—NH—(CH₂)_(s)—,

 H—(C═O)—(CH₂)_(s)—, (C₁-C₆)alkyl-(C═O)—, hydroxy,hydroxy-(C₁-C₆)alkyl-, (C₁-C₆)alkyl-O—(C₁-C₆)alkyl-, or —CN; R¹⁰ ishydrogen or halo; R¹¹ is selected from hydrogen, halo, CF₃, (C₁-C₆)alkyloptionally substituted with one to three halogen atoms, (C₁-C₆)alkoxyoptionally substituted with one to three halogen atoms,(C₁-C₆)alkylthiol, amino-(CH₂)_(p)—, (C₁-C₆)alkyl-NH—(CH₂)_(p)—,di(C₁-C₆)alkyl-N—(CH₂)_(p)—, (C₃-C₇)cycloalkyl-NH—(CH₂)_(p)—,amino-(C₁-C₆)alkyl-NH—(CH₂)_(p)—,(C₁-C₆)alkyl-NH—(C₁-C₆)alkyl-NH—(CH₂)_(p)—,di(C₁-C₆)alkyl-N-(C₁-C₆)alkyl-NH—(CH₂)_(p)—,

 H₂N—(C═O)—(CH₂ _(p)—, (C₁-C₆)alkyl-HN—(C═O)—(CH₂)_(p)—,di(C₁-C₆)alkyl-N—(C═O)—(CH₂)_(p), (C₃-C₇)cycloalkyl-NH—(C═O)—(CH₂)_(p)—,R¹³O—(CH₂)_(p)—, R¹³O—(C═O)—(CH₂)_(p)—, H(O═C)—O—,H(O═C)—O—(C₁-C₆)alkyl-, H(O═C)—NH—(CH₂)_(p)—,(C₁-C₆)alkyl-(O═C)—NH—(CH₂)_(p)—, —CHO, H—(C═O)—(CH₂)_(p)—,(C₁-C₆)alkyl-(C═O)—(CH₂)_(p)—,

 (C₁-C₆)alkyl-(C═O)—O—(CH₂)_(p)—, amino-(C₁-C₆)alkyl-(C═O)—O—(CH₂)_(p)—,(C₁-C₆)alkyl-(C═)—O—(CH₂)_(p)—, amino-(C₁-C₆)alkyl-(C═O)—O—(CH₂)_(p)—,(C₁-C₆)alkyl-(C═O)—O—(CH₂)_(p)—, (C₁-C₆)alkyl-NH—(C₁-C₆)alkyl-(C═O)—O—(CH₂)_(p)—,di(C₁-C₆)alkyl-N—(C₁-C₆)alkyl-(C═O)—O—(CH₂)_(p)—,amino-(C₁-C₆)alkyl-O—(C═O)—(CH₂)_(p)—,(C₁-C₆)alkyl-NH—(C₁-C₆)alkyl-O—(C═O)—(CH₂)_(p)—,di(C₁-C₆)alkyl-N—(C₁-C₆)alkyl-O—(C═O)—(CH₂)_(p)—, hydroxy,hydroxy-(C₁-C₆)alkyl-, hydroxy-(C₁-C₆)alkyl-NH—(CH₂)_(p)—,(C₁-C₆)alkyl-O—(C₁-C₆)alkyl-, —CN, piperidine-(CH₂)_(p)—,pyrrolidine-(CH₂)_(p)—, and 3-pyrroline-(CH₂)_(p)—, wherein saidpiperidine, pyrrolidine and 3-pyrroline moieties of saidpiperidine-(CH₂)_(p)—, pyrrolidine-(CH₂)_(p)— and 3-pyrroline-(CH₂)_(p)—groups may optionally be substituted on any of the ring carbon atomscapable of supporting an additional bond, with zero to two substituents,with a substituent independently selected from halo, CF₃, (C₁-C₆)alkyloptionally substituted with one to three halogen atoms, (C₁-C₆)alkoxyoptionally substituted with one to three halogen atoms,(C₁-C₆)alkylthiol, amino-(CH₂)_(p)—, (C₁-C₆)alkyl-NH—(CH₂)_(p)—,di(C₁-C₆)alkyl-N—(CH₂)_(p)—, (C₃-C₇)cycloalkyl-NH—(CH?)_(p)—,amino-(C₁-C₆)alkyl-NH—(CH₂)_(p)—,(C₁-C₆)alkyl-NH—(C₁-C₆)alkyl-NH-CH₂)_(p)—,di(C₁-C₆)alkyl-N—(C₁-C₆)alkyl-NH—(CH₂)_(p)—,(C₁-C₆)alkyl—O—(C₁-C₆)alkyl-,

 H₂N(C═O)—(CH₂)_(p)—, (C₁-C₆)alkyl-HN—(C═O)—(CH₂)_(p)—,di(C₁-C₆)alkyl-N—(C═O)—(CH₂)_(p), (C₃-C₇)cycloalkyl-NH—(C═O)—(CH₂)_(p)—,R¹³O—(CH₂)_(p)—, R¹³)—(C═O)—(CH₂)_(p)—, H(O═C)—O—,H(O═C)—O—(C₁-C₆)alkyl-, H(O═C)—NH—(CH₂)_(p)—,(C₁-C₆)alkyl-(O═)NH—(CH₂)_(p)—, —CHO, H—(C═O)—(CH₂)_(p)—,(C₁-C₆)alkyl-(C═O)—,

 (C₁-C₆)alkyl-(C═O)—O—NH—(CH₂)_(p)—,amino-(C₁-C₆)alkyl-(C═O)—O—(CH₂)_(p)—,(C₁-C₆)alkyl-NH—(C₁-C₆)alkyl-(C═O)—O—(CH₂)_(p)—,di(C₁-C₆)alkyl-N—(C₁-C₆)alkyl-(C═O)—O—(CH₂)_(p)—, hydroxy,hydroxy-(C₁-C₆)alkyl-, hydroxy-(C₁-C₆)alkyl-NH—(CH₂)_(p)—, and —CN; R¹²is hydrogen, —CN or halo; each p is independently an integer from zeroto 4; and s is an integer from zero to 4; wherein the dashed bondrepresents a double bond; or the pharmaceutically acceptable salts ofsuch compounds.
 2. A compound according to claim 1 wherein R³ ishydrogen, halo or (C₁-C₆)alkyl.
 3. The compound according to claim 1wherein “B” is nitrogen, “A” and “D” are carbon and R³ is hydrogen.
 4. Acompound according to claim 1 wherein R⁵ is chloro or methyl.
 5. Acompound according to claim 3 wherein n is one and R⁵ is a substituentortho to the asterisked carbon.
 6. The compound according to claim 1wherein R⁹ is fluoro, chloro, —CN or hydroxy; or R¹¹ is —CHO, chloro,fluoro, methyl, (C₁-C₆)alkyl-NH—(CH₂)_(p)—, di(C₁-C₆)alkyl-N—(CH₂)_(p)—,or cyano.
 7. The compound according to claim 2 wherein R⁹ is fluoro,chloro, —CN or hydroxy; or R¹¹ is —CHO, chloro, fluoro, methyl,(C₁-C₆)alkyl-NH—(CH₂)_(p)—, di(C₁-C₆)alkyl-N—(CH₂)_(p)—, or cyano.
 8. Acompound according to claim 1 wherein R² is heteroaryl and saidheteroaryl is either an six-membered heterocycle wherein “K”, “L” and“M” are carbon, or “K” and “L” are carbon and “M” is nitrogen, or saidheteroaryl is an five membered heterocycle wherein “T” is nitrogen, “P”is sulfur and “Q” is carbon, or “T” is nitrogen or sulfur, “Q” isnitrogen or sulfur and “P” is carbon or “T” is oxygen and “P” and “Q”are each carbon.
 9. The compound according to claim 1 wherein saidcompound is selected from the group consisting of:(S)-6-fluoro-2-[2-(2-fluoro-phenyl)-vinyl-3-(2-methyl-pyridin-3-yl)-3H-quinazolin-4-one;(S)-2-{2-[6-fluoro-3-(2-methyl-pyridin-3-yl)-4-oxo-3,4-dihydro-quinazolin-2-yl]-vinyl}-benzonitrile;(S)-2-{2-[6-fluoro-3-(2-methylpyridin-3-yl)-4-oxo-3,4-dihydroquinazolin-2-yl]-vinyl}-benzonitrile;(S)-2-{(2-chloro-pyridin-3-yl)-6-fluoro-4-oxo-3,4-dihydroquinazol-in-2-yl]-vinyl}-benzonitrile;(S)-2-{2-[6-fluoro-3-(2-methyl-pyridin-3-yl)-4-oxo-3,4-dihydro-quinazolin-2yl]-vinyl}-4-methyl-benzonitrile;(S)-2-[2-(5-diethylaminomethyl-2-fluoro-phenyl)-vinyl]-6-fluoro-3-(2-methyl-pyridin-3-yl)-3H-quinazolin-4-one,or(S)-6-fluoro-2-[2-(2-fluoro-5-pyrrolidin-1-ylmethyl-phenyl)-vinyl]-3-(2-methyl-pyridin-3-yl)-3H-quinazolin-4-one.10. A pharmaceutical composition for treating a condition selected fromepilepsy and convulsions, in a mammal, comprising an amount of acompound according to claim 1 effective in treating such condition and apharmaceutically acceptable carrier.
 11. A method for treating acondition selected from epilepsy and convulsions, in a mammal,comprising administering to a mammal requiring such treatment an amountof a compound according to claim 1 effective in treating such condition.12. A pharmaceutical composition for treating a condition selected fromepilepsy and convulsions, in a mammal, comprising an AMPA receptorantagonizing effective amount compound according to claim 1 and apharmaceutically acceptable carrier.
 13. A method for treating acondition selected from epilepsy and convulsions, in a mammal,comprising administering to a mammal requiring such treatment an AMPAreceptor antagonizing effective amount of a compound according to claim1.